N-(1-arylpyrazol-4l)sulfonamides and their use as parasiticides

ABSTRACT

The invention relates to a sulfonamide compound of formula (I) or a pharmaceutically, veterinarily or agriculturally acceptable salt or solvate thereof, where the groups R 1 -R 5  are described in the description, to compositions comprising such compounds, processes for their synthesis and their use as parasiticides.

The present invention relates to pesticidal compounds and a process fortheir preparation. More particularly, the present invention relates toN-(1-arylpyrazol-4-yl)sulfonamides which possess antiparasitic activity.In particular, we have identified a series ofN-(1-arylpyrazol-4-yl)sulfonamides which have improved activity and/or alonger duration of action and/or improved safety.

Sulphamoyl (reversed sulphonamides) arylpyrazoles for the control ofarthropod, plant nematode, or helminth pests have also been disclosedin, for example, EP-234119, U.S. Pat. No. 2,002,016333, WO-0258690 andDE-19511269.

5-sulphonamido-1-arylpyrazoles have been disclosed as having utility asherbicides in, for example, EP-0192951 and EP-302328.

U.S. Pat. No. 5,618,945 relates to a process for sulphinylation ofcompounds such as arylpyrazoles, by the treatment of a compound such asRS(O)X, where X is commonly Cl, and discloses compounds of formulaR—S(O)NH-Het where Het can be N-arylpyrazole, although it is not clearwhich substitution pattern is referred to.

Some pyrazoles possessing bactericidal activity are disclosed inWO-9315060 for use in crop protection. Among the many structuresdisclosed are some N-heterocyclic pyrazol-4-yl sulfonamides.

WO00/71532, WO03/51833, WO01/19788, WO01/19798, WO03/37274, WO04/00318,WO98/57937 and WO96/12706 all generally describe pyrazole compounds foruses unrelated to those described for the present invention.

The prior art compounds do not always demonstrate good activity or along duration of action against parasites. Similarly, some parasiticidalagents are useful only for a narrow spectrum of parasites. Modernpesticides must meet many demands, including long duration, broadspectrum of action, low toxicity, combination with other activesubstances and/or different formulation excipients. The occurrence ofresistance is also possible. Consequently the search for newantiparasitic agents is ongoing and there is a constant demand for novelcompounds which are advantageous over the known compounds in one or moreof these aspects.

The aim of the present invention is to provide a compound which can beconveniently administered as an antiparasitic agent. In particular anagent is sought which can be used in the treatment of human or animalparasitic diseases or can be used in agricultural or horticulturalapplications. One aim is to provide an agent which can be used inhumans, livestock (including sheep, pigs and cattle), companion animals(including cats, dogs and horses). The agent is intended to controlarthropods, arachnids, nematodes and helminths including flies, fleas,mites and ticks.

Another aim is to provide compounds with good pharmacokinetics andextended duration of action and thus which prevents re-establishment ofinfestation over long periods of time.

It is a further aim to provide a compound suitable for oral, parenteralor topical administration which is able to kill existing parasites andprevent infestation. This has benefits in terms of compliance and labourcosts as less frequent dosing is needed and the dosing timetable iseasier. This in turn assists in minimising the re-incidence ofinfestation as a subsequent dosage is less likely to be overlooked.

It is an aim of the present invention to overcome various disadvantagesof or improve on the properties of prior art compounds. Thus it is anaim of the invention to provide an arylpyrazole which has improvedactivity relative to prior art compounds against parasites. Thecompounds of the present invention have especially good ability tocontrol a broad spectrum of arthropods as shown by the results of testsdemonstrating their potency and efficacy. Surprisingly, we have foundthat the compounds of the present invention are significantly moreactive against fleas and/or have a greater duration of action thansimilar prior art compounds. One advantage of the compounds of thepresent invention is that treatment with these compounds can also leadto a reduced incidence of allergy to the parasite which is responsiblefor the infestation. For example, the incidence of flea allergies whichcan cause flea allergic dermatitis may be reduced.

It is also desirable that the compounds of the present invention shouldhave an improved pharmacokinetic profile, improved safety, longerhalf-life, improved persistence and improved solubility. It is alsodesired that the compounds should lead to a reduced incidence of emesis.

Unfortunately, many potent pesticidal aryl pyrazoles and theirderivatives also have undesirable effects such as emesis on animalsregardless of whether or not the animal itself is being treateddirectly. This unwanted toxicity can limit the dose that can be used andthus limits the range of parasites that can be controlled. Thus it is anaim of the present invention to address the need for the development anduse of new and efficacious pesticides that can control pests for longerperiods of time but which are not toxic to animals susceptible to pestinfestations or animals that might come into contact with areassusceptible to pest infestations.

It is a further aim to provide a convenient, synthetically efficientprocess for the production of the aryl pyrazoles and the intermediatesof the present invention. It is also an aim to provide a route to thecompounds of the invention which offers a good yield and which ideallyavoids the use of unnecessary synthetic steps and/or purification steps.

The present invention satisfies some or all of the above aims.

According to the present invention, there is provided a compound offormula (I) or a pharmaceutically, veterinarily or agriculturallyacceptable salt or solvate thereof,

wherein:R¹ represents phenyl or heteroaryl, optionally substituted by one ormore groups independently selected from halo, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkanoyl, C₁₋₆haloalkanoyl, —S(O)_(n)C₁₋₆alkyl, —S(O)_(n)C₁₋₆haloalkyl andpentafluorothio;R² represents hydrogen, halo, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ haloalkenyl, C₂₋₆ alkynyl, C₂₋₆ haloalkynyl,—S(O)_(n)C₁₋₆ alkyl, —S(O)_(n)C₁₋₆haloalkyl, —(C₀₋₃alkylene)-C₃₋₈cycloalkyl, C₁₋₆ alkanoyl, optionally substituted by C₁₋₆ alkoxy, C₁₋₆haloalkanoyl, optionally substituted by C₁₋₆ alkoxy, phenyl, het,—(C₀₋₃alkylene)-N(R^(a))R^(b), —(C₀₋₃alkylene)-C(O)NR^(a)R^(b) or—(C₀₋₃alkylene)N(R^(c))C(O)R⁸;R³ represents C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆haloalkenyl, —(C₀₋₃alkylene)-C₃₋₈ cycloalkyl,—(C₁₋₃alkylene)-S(O)_(n)C₁₋₆alkyl,—(C₁₋₃alkylene)-S(O)_(n)C₁₋₆haloalkyl, —(C₀₋₃alkylene)-N(R^(a))R^(b),—(C₀₋₃alkylene)-phenyl, —(C₀₋₃alkylene)-het, —(C₂₋₃alkenylene)-phenyl,—(C₂₋₃alkenylene)-het, C₁₋₆ alkanoyl, C₁₋₆ haloalkanoyl orN(R^(c))CO₂R⁸;R⁴ represents hydrogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, —(C₀₋₃alkylene)-R⁷ or—(C₁₋₃alkylene)-R⁸;or R³ and R⁴ taken together with the nitrogen and sulphur atoms to whichthey are attached form a 4 to 7-membered ring;R⁵ represents hydrogen, hydroxy, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ haloalkenyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,—N═C(R¹³)(C₀₋₆alkylene)-R¹¹ or N(R¹²)R¹³;R⁶ represents C₁₋₆ alkyl or C₁₋₆ haloalkyl;R⁷ represents C₃₋₈cycloalkyl, —S(O)_(n)R⁹, phenyl, het, —CO₂R⁶ orC(O)N(R^(a))R^(b);R⁸ represents hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano, —N(R^(a))R¹³or —O—C(O)R⁶;R⁹ represents C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl,—N(R^(a))R^(b), phenyl or het;R¹⁰ represents hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl;R¹¹ represents hydrogen, hydroxy, C₁₋₃alkoxy, —N(R^(a))R^(b), phenyl,het or C₃₋₈cycloalkyl, with the proviso that —N═C(R¹³)(C₀₋₅alkylene)-R¹¹is not N═CH₂;R¹² represents hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkenyl orC₁₋₆ haloalkenyl;R¹³ represents hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkenyl, C₁₋₆haloalkenyl C₃₋₈cycloalkyl, phenyl, het, —(C₁₋₆alkylene)-R¹⁴,—C(O)_(p)R¹⁵ or —CON(R¹⁶)(C₁₋₆alkylene)-R¹⁷;R¹⁴ represents hydroxy, C₁₋₃alkoxy, C₁₋₃haloalkoxy, C₃₋₆cycloalkyl,phenyl, het or —N(R^(a))R^(b);R¹⁵ represents C₁₋₆ alkyl, C₁₋₆ haloalkyl or —(C₁₋₆alkylene)-C₁₋₃alkoxy;R¹⁶ represents hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl;R¹⁷ represents hydrogen or N(R^(a))R^(b);R^(a) and R^(b) independently represent hydrogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl or C₂₋₆ haloalkenyl, or R^(a) additionallyrepresents —(C₀₋₃alkylene)C₃₋₅ cycloalkyl, —(C₀₋₃alkylene)phenyl or—(C₀₋₃alkylene)het, or together R^(a) and R^(b) form a 4- to 7-memberedring, optionally substituted by one or more groups independentlyselected from halo, hydroxy, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy andC₁₋₆haloalkoxy;R^(c) represents hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ haloalkenyl, —(C₀₋₃alkylene)C₃₋₈ cycloalkyl, —(C₀₋₃alkylene)phenylor —(C₀₋₃alkylene)het;n represents an integer selected from 0, 1 and 2;p represents an integer selected from 1 and 2;where het represents a four- to seven-membered heterocyclic group, whichis aromatic or non-aromatic and which contains one or more heteroatomsselected from nitrogen, oxygen, sulfur and mixtures thereof;where heteroaryl represents a 5 or 6 membered aromatic ring whichcontains 1-3 heteroatoms selected from N, O and 5 or 4-N atoms to form atetrazolyl;where both phenyl and het may be optionally substituted, where thevalence allows, by one or more substituents independently selected fromhalo, hydroxy, cyano, nitro, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkenyl,C₁₋₆haloalkenyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₃₋₈ cycloalkyl, C₁₋₆alkanoyl, C₁₋₆ haloalkanoyl, C₁₋₆ alkylcarbonyloxy, C₁₋₆ alkoxycarbonyland NR^(a)R^(b);where C₃₋₈cycloalkyl may be optionally substituted by one or more groupsindependently selected from halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkenyl, C₁₋₆haloalkenyl, hydroxy, C₁₋₆alkoxy and C₁₋₆haloalkoxy; andwhere any alkylene or alkenylene group may be optionally substituted byone or more halo.

According to formula (I), C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy orC₁₋₆haloalkanoyl means a C₁₋₆ alkyl, C₁₋₆ alkoxy or C₁₋₆alkanoylsubstituted by 1 to 5 halo groups chosen independently, suitably fluorogroups. Also, ‘halo’ means a group selected from fluoro, bromo, chloro,bromo or iodo.

According to formula (I), a C₁₋₆ alkyl, C₁₋₆ alkoxy or C₁₋₆alkanoyl,including the corresponding halo substituted groups, may bestraight-chained or, where possible, branched. An alkylene group refersto a straight-chained or, where possible, branched linking group andalkenylene refers to a linking group containing one double bond. For theavoidance of any doubt, a C₀alkylene group refers to a direct linkbetween the connecting groups.

Suitably, R¹ is substituted phenyl, substituted in one or both of the 2-and 6-positions and at the 4-position with a substituent independentlyselected from the group comprising halogen, e.g. chloro, C₁₋₆ alkyl,e.g. methyl, C₁₋₆ haloalkyl, e.g. trifluoromethyl, C₁₋₆ alkoxy, e.g.methoxy, C₁₋₆ alkylthio, e.g. methylthio, C₁₋₆ haloalkoxy, e.g.trifluoromethoxy or difluoromethoxy, C₁₋₆ haloalkylthio, e.g.trifluoromethylthio, and pentafluorothio.

Preferably, R¹ is phenyl substituted at one or both of the 2- and6-positions by halo, e.g. chloro, and at the 4-position by a groupselected from C₁₋₄ alkyl substituted with one or more independentlyselected halo groups, e.g. trifluoromethyl, C₁₋₄ alkoxy substituted withone or more independently selected halo atoms, e.g. trifluoromethoxy ordifluoromethoxy, C₁₋₆ alkylthio substituted with one or moreindependently selected halo atoms, e.g. trifluoromethylthio, andpentafluorothio.

More preferably, R¹ is a phenyl group which bears chloro substituents atthe 2- and 6-positions, and a substitutent at the 4-position selectedfrom trifluoromethyl, difluoromethoxy, trifluoromethoxy,trifluoromethylthio and pentafluorothio.

Still more preferably, R¹ is a phenyl group in which the 2- and6-substituents are chloro and the 4-substituent is selected fromtrifluoromethyl and pentafluorothio.

Where R¹ is a heteroaryl, R¹ is suitably a 3,5-disubstitutedpyridin-2-yl, wherein the 3-substituent is selected from hydrogen andhalo, and the 5-substituent is selected from halo, e.g. chloro,pentafluorothio, S(O)_(n)C₁₋₆ alkyl, S(O)_(n)C₁₋₆ haloalkyl, C₁₋₆ alkyl,C₁₋₆ haloalkyl, e.g. trifluoromethyl, C₁₋₆ alkoxy and C₁₋₆ haloalkoxy.

Suitably, het represents an optionally substituted aromatic ornon-aromatic 5- or 6-membered heterocyclic group containing 1, 2 or 3heteroatoms, which are independently selected from N, O or S atoms. Moresuitably, het is selected from pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, furanyl, thiophenyl, pyrrolyl,triazolyl, oxadiazolyl, azetidinyl, pyrrolidyl, piperidyl, pyridyl,pyrazinyl, pyrimidyl and morpholinyl, wherein the aforementioned groupsmay be optionally substituted by one or more groups independentlyselected from C₁₋₆ alkyl, e.g. methyl, C₁₋₆ haloalkyl, e.g.trifluoromethyl, halogen, e.g. fluoro, and N(R^(a))R^(b), e.g. amino.

Suitably, R² is selected from hydrogen, cyano, C₁₋₆ haloalkyl, e.g.trifluoromethyl, C₃₋₈ cycloalkyl, e.g. cyclopropyl, C₁₋₆ alkanoyl, e.g.acetyl, and —C(O)N(R^(a))R^(b), e.g. aminocarbonyl.

More preferably, R² is selected from hydrogen, trifluoromethyl,cyclopropyl, acetyl, aminocarbonyl and cyano. Yet more preferably, R² isselected from trifluoromethyl and cyano. Most preferably, R² is cyano.

When R³ is —(C₀₋₃alkylene)-N(R^(a))R^(b), suitably the N— is directlylinked and N(R^(a))R^(b) is suitably amino or di-C₁₋₆ alkylamino, e.g.N,N-dimethylamino.

Suitably, R³ is selected from C₁₋₆ alkyl, e.g. methyl, ethyl, n-propylor i-propyl, C₁₋₆ haloalkyl, e.g. trifluoromethyl or2,2,2-trifluoroethyl, C₃₋₈cycloalkyl, e.g. cyclopropyl,—(C₁₋₃alkylene)-S(O)_(n)C₁₋₆alkyl, e.g. methylsulfonylmethyl or1-methylsulfonylethyl, N(R^(a))R^(b), e.g. amino or N,N-dimethylamino,—N(R^(c))CO₂R⁶, e.g. tert-butoxycarbonylamino, optionally substitutedphenyl, e.g. by one or more halo, e.g. fluoro, optionally substitutedbenzyl, e.g. by one or more halo, e.g. fluoro, —(C₂₋₃alkenylene)-phenyl,e.g. 2-phenylethenyl, and C₁₋₆alkanoyl, e.g. propan-2-oyl.

Preferably, R³ is selected from C₁₋₆ alkyl, e.g. methyl, ethyl, n-propylor i-propyl, C₁₋₆ haloalkyl, e.g. trifluoromethyl or2,2,2-trifluoroethyl, C₃₋₈ cycloalkyl, e.g. cyclopropyl,—(C₁₋₃alkylene)-S(O)_(n)C₁₋₆alkyl, e.g. methylsulfonylmethyl,—N(R^(a))R^(b), e.g. amino or N,N-dimethylamino, C₁₋₆ alkanoyl, e.g.propan-2-oyl, —N(R^(a))CO₂R⁶, e.g. tert-butoxycarbonylamino, phenyl,optionally substituted by one or more halo, e.g. 3,4-difluorophenyl, andbenzyl.

More preferably, R³ is selected from methyl, ethyl, trifluoromethyl and2,2,2-trifluoroethyl. Most preferably, R³ is methyl.

Where R⁴ is —(C₀₋₃alkylene)-R⁷, the link is suitably a direct or amethylene link.

Where R⁴ is —(C₁₋₃alkylene)-R⁸, the link is suitably a methylene orethylene link.

Where R⁴ represents —(C₀₋₃alkylene)-S(O)_(n)R⁹, n is suitably 0 or 2,preferably 2, and R⁹ is suitably selected from C₁₋₆ alkyl, e.g. methyl,C₁₋₆ haloalkyl, e.g. trifluoromethyl or 2,2,2-trifluoroethyl, C₃₋₈cycloalkyl, e.g. cyclopropyl, N(R^(a))R^(b), e.g. amino orN,N-dimethylamino, and phenyl, optionally substituted by one or morehalo, e.g. fluoro.

Preferably, n is 2, C₀₋₃alkylene is a direct link and R⁹ represents C₁₋₆alkyl, e.g. methyl, or C₁₋₆ haloalkyl, e.g. trifluoromethyl or2,2,2-trifluoroethyl.

Where R⁴ represents —(C₀₋₃alkylene)-C₃₋₈ cycloalkyl, C₀₋₃alkylene issuitably a direct link or methylene, C₃₋₈ cycloalkyl suitably representscyclopropyl, cyclobutyl or cyclopentyl, optionally substituted by one ormore halo, e.g. fluoro, C₁₋₆ alkyl, e.g. methyl or C₁₋₆ haloalkyl, e.g.trifluoromethyl. Where R⁴ represents —(C₀₋₃alkylene)-C₃₋₈ cycloalkyl, apreferred group is 1-(trifluoromethyl)cyclopropylmethyl.

When R⁴ represents —(C₀₋₃alkylene)-het, the link is suitably a methyleneor ethylene link and het is suitably selected from pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl,thiophenyl, pyrrolyl, triazolyl, oxadiazolyl, pyrrolidyl, pyridyl,pyrazinyl, pyrimidyl and morpholinyl, wherein the aforementioned groupsmay be optionally substituted by one or more groups independentlyselected from C₁₋₆ alkyl, e.g methyl, halogen, e.g. fluoro, andN(R^(a))R^(b), e.g. amino. Preferably, when R⁴ represents(C₁₋₂alkylene)-het, het is selected from pyrazolyl, imidazolyl,isoxazolyl, pyrrolyl, triazolyl, oxadiazolyl, pyrrolidyl, pyridyl,pyrazinyl, pyrimidyl and morpholinyl, wherein the aforementioned groupsmay be optionally substituted by one or more groups independentlyselected from C₁₋₆ alkyl, halogen, e.g. fluoro, and N(R^(a))R^(b), e.g.amino. More preferably, when R⁴ represents —(C₀₋₃alkylene)-het,C₀₋₃alkylene is a methylene link and het is selected from imidazolyl,isoxazolyl, oxadiazolyl and pyridyl, where each ring may be optionallysubstituted by C₁₋₆ alkyl, e.g. methyl.

When R⁴ represents —(C₀₋₃alkylene)-phenyl, phenyl is suitably optionallysubstituted by one or more halo, e.g. fluoro, e.g. 4-fluoro.

When R⁴ represents —(C₁₋₃alkylene)-N(R^(a))R^(b), this is suitably2-N,N-dimethylaminoethyl.

When R⁴ represents —(C₁₋₃alkylene)-C(O)N(R^(a))R^(b), this is suitablyaminocarbonylmethyl.

Suitably, R⁴ is selected from hydrogen, C₁₋₆ alkyl, e.g. methyl, ethylor isopropyl, C₁₋₆ haloalkyl, e.g. trifluoromethyl,2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-fluoroethyl or2,2,3,3,3-pentafluoropropyl, (C₀₋₃alkylene)-C₃₋₈ cycloalkyl, e.g.cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl,(1-methylcyclopropyl)methyl, 2,2-difluorocyclopropyl or1-(trifluoromethyl)cyclopropylmethyl, cyanomethyl, 2-hydroxyethyl,(C₁₋₂alkylene)-het, e.g. pyrazol-3-ylmethyl, pyrimidin-4-ylmethyl,pyridin-3-ylmethyl, 2-pyrrolidin-1-ylethyl, 2-morpholin-4-ylethyl,1-methyl-1H-imidazol-2-ylmethyl, pyridin-4-ylmethyl, triazolylethyl,1,2,4-oxadiazol-3-ylmethyl, pyridin-2-ylmethyl or(5-methylisoxazoly-3-yl)methyl, (C₀₋₃alkylene)-phenyl, e.g. benzyl or4-fluorobenzyl, (C₀₋₁alkylene)-S(O)_(n)R⁹, e.g.1,1,1-trifluoromethylsulfonyl, aminosulfonyl, N,N-dimethylaminosulfonyl,cyclopropylsulfonyl, methylsulfonyl, 4-fluorophenylsulfonyl,2,4-difluorophenylsulfonyl, (methylsulfonyl)methyl or2,2,2-trifluoroethylsulfonyl, (C₁₋₃alkylene)-O—C(O)R⁶, e.g.tert-butylcarbonyloxymethyl, (C₁₋₃alkylene)-C(O)N(R^(a))R^(b), e.g.aminocarbonylmethyl, and —CO₂R⁶, e.g. methoxycarbonyl.

More preferably, R⁴ is selected from hydrogen, methyl, ethyl,trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,methylsulfonyl, trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl,aminosulfonyl, N,N-dimethylaminosulfonyl, methylsulfonymethyl,cyclopropyl, cyclobutyl, cyclopropylmethyl,1-(trifluoromethyl)cyclopropylmethyl, cyanomethyl, methoxycarbonyl,triazolylethyl, pyrimidin-4-ylmethyl, 1,2,4-oxadiazol-3-ylmethyl,pyrazol-3-ylmethyl, 5-methyl-isoxazol-3-ylmethyl, 2-pyridin-4-ylethyl,aminocarbonylmethyl, benzyl and 4-fluorobenzyl.

Where R³ and R⁴ form a 4 to 7 membered ring, this is suitably adioxidoisothiazolidinyl group, e.g. 1,1-dioxidoisothiazolidin-2-yl, or adioxido-thiazinanyl group, e.g. 1,1-dioxido-1,2-thiazinan-2-yl group.

Where R⁵ is —N═C(R¹⁰)(C₀₋₅alkylene)-R¹¹, R¹⁰ is suitably hydrogen andthe C₀₋₅alkylene is suitably a direct link. R¹¹ is suitably C₁₋₃alkoxy,e.g. ethoxy, —N(R^(a))R^(b), e.g. N,N-dimethyl, or phenyl, optionallysubstituted by one or more hydroxy.

R¹² is suitably hydrogen or methyl, preferably hydrogen.

Where R¹³ represents —(C₁₋₆alkylene)-R¹⁴, the C₁₋₆alkylene is suitably amethylene, ethylene or propylene link and R¹⁴ is suitably C₁₋₄alkoxy,e.g. ethoxy, phenyl, —N(R^(a))R^(b), e.g. N,N-dimethylamino, het, e.g.pyrrolidinyl, morpholinyl, azetidinyl, piperidinyl or pyridyl, orC₃₋₈cycloalkyl, e.g. cyclopropyl.

Where R¹³ represents C(O)_(p)R¹⁵ and p represents 1, R¹⁵ is suitablyC₁₋₆alkyl, e.g. methyl. When p represents 2, R¹⁵ is suitably C₁₋₆alkyl,e.g. methyl, or C₁₋₆haloalkyl, e.g. 2,2,2-trifluoroethyl.

Where R¹³ represents —C(O)N(R¹⁶)(C₁₋₆alkylene)-R¹⁷, R¹⁶ is suitablyhydrogen and C₁₋₆alkylene is suitably ethylene. R¹⁷ is suitably amino.

R¹³ is suitably selected from hydrogen, methyl, benzyl,cyclopropylmethyl, 2-N,N-dimethylaminoethyl, acetyl,methoxymethylcarbonyl, methoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl,N-pyrrolidinylethyl, N-morpholinylethyl, N-piperidinylethyl,pyridin-4-ylmethyl, N-azetidinylethyl and aminoethylaminocarbonyl. R¹³is preferably hydrogen and R¹² and R¹³ are preferably both hydrogen.

Suitably, R⁵ is selected from hydrogen, halo, e.g. chloro, C₁₋₆ alkoxy,e.g. methoxy, —N═C(H)R¹¹, where R¹¹ is ethoxy, N,N-dimethyl or phenyl,optionally substituted by one or more hydroxy, e.g. 2,4-di-hydroxy, and—NR¹²R¹³, e.g. amino, benzylamino, pyridin-4-ylmethylamino,2-ethoxyethylamino, methylamino, methoxymethylcarbonylamino,cyclopropylmethylamino, methylcarbonylamino,2-N,N-dimethylaminoethyl(methyl)amino, 2-N-azetidinylethylamino,2-N-pyrrolidinylethylamino, 2-N-morpholinoethylamino,2-N-piperidinylethylamino, cyclopropylmethylamino, methoxycarbonylamino,2,2,2-trifluoroethoxycarbonylamino and 2-aminoethylaminocarbonylamino.

Preferably, R⁵ is selected from hydrogen, amino,methoxymethylcarbonylamino, cyclopropylmethylamino,3-N,N-dimethylaminopropylamino, 2-N-azetidinylethylamino,2-N-piperidinylethylamino, 2-N-pyrrolidinylethylamino,2-N-morpholinoethylamino, methoxycarbonylamino, ethoxyimino, phenyliminoand 2,4-dihydroxyphenylimino. Most preferably, R⁵ is amino.

A suitable sub-group of the present invention is represented bycompounds of formula (Ia),

whereinR^(1a) is aryl or heteroaryl optionally substituted by one or moregroups independently selected from: hydrogen; halo; C₁₋₆ alkyl; C₁₋₆alkoxy which may be optionally substituted with one or moreindependently selected halo atoms; —S(O)_(na)C₁₋₆ alkyl; andpentafluorothio; cyano; C₁₋₆ alkanoyl which may be optionallysubstituted with one or more independently selected halo atoms;R^(2a) is selected from: hydrogen; halo; C₁₋₆ alkyl; —S(O)_(na)C₁₋₆alkyl; —(CH₂)_(ma)C₃₋₈ cycloalkyl which may be optionally substitutedwith one or more substituents independently selected from: halo and C₁₋₆alkyl; cyano; nitro; —(CH₂)_(ma)NR^(aa)R^(ba); alkanoyl which may beoptionally substituted by one or more groups independently selected fromhalo and C₁₋₄ alkoxy; phenyl; oxadiazole; —C(O)NR^(aa)R^(ba);—NR^(aa)C(O)R^(ba); C₂₋₆ alkenyl; and C₂₋₆ alkynyl;R^(3a) is selected from: C₁₋₆ alkyl; —(CH₂)_(m)NR^(aa)R^(ba);—(CH₂)_(ma)C₃₋₈ cycloalkyl which may be optionally substituted with oneor more substituents independently selected from: halo and C₁₋₆ alkyl;—(CH₂)_(ma) phenyl; —CH═CH-phenyl; and —(CH₂)_(ma) het;R^(4a) is selected from: hydrogen; C₁₋₆ alkyl; —(CH₂)_(ma)C₃₋₈cycloalkyl which may be optionally substituted with one or moresubstituents independently selected from: halo and C₁₋₆ alkyl;—(CH₂)_(ma)S(O)_(p)R^(6a); —CO₂(C₁₋₆ alkyl); —(CH₂)_(ma) het; and—C(O)NR^(aa)R^(ba);or R^(3a) and R^(4a) taken together with the nitrogen and sulphur atomsto which they are attached form a 4 to 7-membered ring;R^(5a) is selected from: hydrogen; hydroxy; C₁₋₆ alkyl; NR^(aa)R^(ba);halo and C₁₋₆ alkoxy;R^(6a) is selected from: C₁₋₆ alkyl; NR^(aa)R^(ba); C₃₋₈ cycloalkylwhich may be optionally substituted with one or more substituentsindependently selected from: halo and C₁₋₆ alkyl; het; and phenyl;each na is independently 0, 1 or 2;each ma is independently 0, 1, 2 or 3;pa is 1 or 2;and whereinhet represents a four- to seven-membered heterocyclic group, which isaromatic or non-aromatic and which contains one or more heteroatomsselected from nitrogen, oxygen, sulfur and mixtures thereof, and whereinsaid heterocyclic ring is optionally substituted and/or terminated wherethe valence allows with one or more substituents selected from: halo,cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, OC(O)C₁₋₆ alkyl,C(O)C₁₋₆ alkyl, C(O)OC₁₋₆ alkyl, and NR^(aa)R^(ba);each C₁₋₆ alkyl group can independently be branched or unbranched andoptionally substituted by one or more groups selected independentlyfrom: cyano; halo; hydroxy; nitro; C₁₋₆ alkoxy; NR^(aa)R^(ba); S(O)_(na)C₁₋₆ alkyl; S(O)_(na) C₃₋₆ cycloalkyl; S(O)_(na)C₁₋₆ alkylhet; C₃₋₈cycloalkyl; and phenyl;each phenyl may be optionally substituted by one or more substituentsindependently selected from: cyano; halo; hydroxy; nitro; C₁₋₆ alkyl;C₁₋₆ haloalkyl; and C₁₋₆ alkoxy; and each R^(aa) and R^(ba) areindependently selected from hydrogen; C₁₋₆ alkyl; and C₃₋₈ cycloalkylwhich may be optionally substituted with one or more substituentsindependently selected from: halo and C₁₋₆ alkyl; or R^(aa) and R^(ba)may be taken together with the nitrogen atom to which they are attachedto form a 4 to 7-membered ring.

A suitable group of compounds of formula (I) of the present inventionare those wherein:

-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2-difluoroethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-1,1,1-trifluoro-N-methylmethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-3,4-difluorobenzenesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}cyclopropanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(cyclopropylmethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(cyanomethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(pyridin-2-ylmethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-benzylmethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-[2-(dimethylamino)ethyl]methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-1-(methylsulfonyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(2-hydroxyethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-isopropylmethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N,N′,N′-trimethylsulfamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-[(methylthio)methyl]methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-[(5-methylisoxazol-3-yl)methyl]methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(cyclopropylmethyl)-N′,N′-dimethylsulfamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-{[1-(trifluoromethyl)cyclopropyl]methyl}methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(cyclobutyl    methyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)cyclopropanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-[(dimethylamino)sulfonyl]methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2,2,2-trifluoro-N-(methylsulfonyl)ethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-1,1,1-trifluoro-N-{[1-(trifluoromethyl)cyclopropyl]methyl}methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-methylmethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}ethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N,N-dimethylsulfamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-1-phenylmethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2,2,2-trifluoroethanesulfonamide;-   (E)-N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2-phenylethylenesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}propane-1-sulfonamide;-   N-[5-amino-1-[2,6-dichloro-4-pentafluorothiophenyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl]-N-(methylsulfonyl)methanesulfonamide;-   N-[5-amino-1-[2,6-dichloro-4-pentafluorothiophenyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl]methanesulfonamide;-   5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(1,1-dioxidoisothiazolidin-2-yl)-1H-pyrazole-3-carbonitrile;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-1,1,1-trifluoro-N-methylmethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(cyclopropylmethyl)-1,1,1-trifluoromethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-ethylmethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-cyclobutylmethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-cyclopentylmethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-1,1,1-trifluoro-N-(methylsulfonyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-[(methylsulfonyl)methyl]methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-cyclobutyl-1,1,1-trifluoromethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-1,1,1-trifluoro-N-isopropyl    methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-cyclopentyl-1,1,1-trifluoromethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}propane-2-sulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-1,1,1-trifluoro-N-methylmethanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-[(5-methylisoxazol-3-yl)methyl]methanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2,2,2-trifluoroethanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2,2,2-trifluoro-N-(methylsulfonyl)ethanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-{[1-(trifluoromethyl)cyclopropyl]methyl}methanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}methanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-2,2,2-trifluoro-N-(methylsulfonyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(2,2-difluorocyclopropyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-[2-(1H-1,2,4-triazol-1-yl)ethyl]methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-1,1,1-trifluoromethanesulfonamide;-   5-amino-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-(1,1-dioxidoisothiazolidin-2-yl)-1H-pyrazole-3-carbonitrile;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-[(1-methylcyclopropyl)methyl]methanesulfonamide;-   5-amino-4-[bis(methylsulfonyl)amino]-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazole-3-carboxamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;-   N-(5-amino-3-cyano-1-{2,6-dichloro-4-[(trifluoromethyl)thio]phenyl}-1H-pyrazol-4-yl)-N-(methylsulfonyl)methanesulfonamide;-   N-{3-acetyl-5-amino-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;-   N-(5-amino-3-cyano-1-{2,6-dichloro-4-[(trifluoromethyl)thio]phenyl}-1H-pyrazol-4-yl)methanesulfonamide;-   N-(5-amino-3-cyano-1-{2,6-dichloro-4-[(trifluoromethyl)thio]phenyl}-1H-pyrazol-4-yl)-N-(2,2,2-trifluoroethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-{[1-(trifluoromethyl)cyclopropyl]methyl}methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)ethanesulfonamide;-   methyl    5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl(methylsulfonyl)carbamate;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-methylmethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2-fluoroethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-[(3-methylisoxazol-5-yl)methyl]methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(pyridin-2-ylmethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(pyridin-4-ylmethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(1,2,4-oxadiazol-3-ylmethyl)methanesulfonamide;

N²-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N²-(methylsulfonyl)glycinamide;

-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-isopropylmethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(pyridin-3-ylmethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(1H-1-pyrazol-3-ylmethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2,3,3,3-pentafluoropropyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2-pyrrolidin-1-ylethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2-morpholin-4-ylethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-methylethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-methylpropane-1-sulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-methylcyclopropanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2,2,2-trifluoro-N-methylethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-[(5-methylisoxazol-3-yl)methyl]methanesulfonamide;-   [{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}(methylsulfonyl)amino]methyl    pivalate;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-ethylmethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-benzylmethanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(4-fluorobenzyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-1-(methylsulfonyl)ethanesulfonamide;-   N-{5-amino-1-[2-chloro-4-pentafluorothio-phenyl]-3-cyano-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;-   5-amino-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-(1,1-dioxido-1,2-thiazinan-2-yl)-1H-pyrazole-3-carbonitrile;-   N-{5-(benzylamino)-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-[(ethoxymethyl)amino]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-(methylamino)-1H-pyrazol-4-yl}methanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-[(methylsulfonyl)(2,2,2-trifluoroethyl)amino]-1H-pyrazol-5-yl}-2-methoxyacetamide;-   ethyl    4-[bis(methylsulfonyl)amino]-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-5-ylimidoformate;-   N-{3-cyano-5-[(cyclopropylmethyl)amino]-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}methanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-[(methylsulfonyl)(2,2,2-trifluoroethyl)amino]-1H-pyrazol-5-yl}acetamide;-   N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-methoxy-1H-pyrazol-4-yl}methanesulfonamide;-   N-[3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-(methylamino)-1H-pyrazol-4-yl]-N-(methylsulfonyl)methanesulfonamide;-   N-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)-N-(methylsulfonyl)methanesulfonamide;-   N-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[2-(dimethylamino)ethyl]amino}-1H-pyrazol-4-yl)-N-(methylsulfonyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N,    (2,2,2-trifluoroethylsulfonyl)-2,2,2-trifluoroethanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-[(2-pyrrolidin-1-ylethyl)amino]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-[(2-morpholin-4-ylethyl)amino]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-[(2-piperidin-1-ylethyl)amino]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;-   N-[3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-(methylamino)-1H-pyrazol-4-yl]-N-(methylsulfonyl)methanesulfonamide;-   N-{3-cyano-5-[(cyclopropylmethyl)amino]-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;-   N-{5-amino-3-cyclopropyl-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;-   N-{5-amino-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}methanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-[(pyridin-4-ylmethyl)amino]-1H-pyrazol-4-yl}methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(aminosulfonyl)methanesulfonamide;-   tert-butyl    ({5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}amino)sulfonylcarbamate;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2-pyridin-4-ylethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(pyrazin-2-ylmethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-[(6-aminopyridin-3-yl)methyl]methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(pyrimidin-4-ylmethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(1-pyridin-4-ylethyl)methanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-2-oxo-N-(2,2,2-trifluoroethyl)propane-1-sulfonamide;-   N-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[3-(dimethylamino)propyl]amino}-1H-pyrazol-4-yl)-N-(2,2,2-trifluoroethyl)methanesulfonamide;-   N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-[(2-piperidin-1-ylethyl)amino]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)sulfamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}sulfamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-4-fluoro-N-(methylsulfonyl)benzenesulfonamide;-   N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2,4-difluoro-N-(methylsulfonyl)benzenesulfonamide;-   methyl    3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-[(methylsulfonyl)(2,2,2-trifluoroethyl)amino]-1H-pyrazol-5-ylcarbamate;-   2,2,2-trifluoroethyl    3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-[(methylsulfonyl)(2,2,2-trifluoroethyl)amino]-1H-pyrazol-5-ylcarbamate;-   N-{5-({[(2-aminoethyl)amino]carbonyl}amino)-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide;-   trifluoroacetate salt of    N-{5-[(2-azetidin-1-ylethyl)amino]-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide;-   N-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(2,4-dihydroxyphenyl)methylene]amino}-1H-pyrazol-4-yl)-N-(2,2,2-trifluoroethyl)methanesulfonamide;-   N-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[phenylmethylene]amino}-1H-pyrazol-4-yl)-N-(2,2,2-trifluoroethyl)methanesulfonamide;-   N-{5-chloro-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide;    or-   N-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[3-(dimethylamino)ethyl]amino}-1H-pyrazol-4-yl)-N-(methylsulfonyl)methanesulfonamide;    or a pharmaceutically, veterinarily or agriculturally acceptable    salt or solvate thereof.

Compounds of formula (I) possess parasiticidal activity in humans,animals and agriculture. They are particularly useful in the control ofectoparasites.

In a further aspect, the present invention provides a process for thepreparation of a compound of formula (I), or a pharmaceutically,veterinarily or agriculturally acceptable salt thereof, or apharmaceutically, veterinarily, or agriculturally acceptable solvate(including hydrate) of either entity, as illustrated below.

The following processes are illustrative of the general syntheticprocedures which may be adopted in order to obtain the compounds of theinvention.

When one or more of R¹, R², R³, R⁴ and R⁵ contain reactive functionalgroups then additional protection may be provided according to standardprocedures during the synthesis of compounds of formula (I). In theprocesses described below, for all synthetic precursors used in thesynthesis of compounds of formula (I), the definitions of R¹, R², R³,R⁴, and R⁵, wherein R¹, R², R³, R⁴, and R⁵ are as defined for formula(I), are intended to optionally include suitably protected variants, P¹,P², P³, P⁴ and P⁵. Such suitable protecting groups for thesefunctionalities are described in the references listed below and the useof these protecting groups where needed is specifically intended to fallwithin the scope of the processes described in the present invention forproducing compounds of formula (I) and its precursors. When suitableprotecting groups are used, then these will need to be removed to yieldcompounds of formula (I). Deprotection can be effected according tostandard procedures including those described in the references listedbelow.

For example, when R⁵ in formula (I) is an unsubstituted amino group,certain precursors may require protection of the amino group in order toperform the necessary transformations, for example, by an imidoformamidegroup such as a compound of formula (Ib), where R¹-R⁴ are as describedfor formula (I) and R⁵ represents —N═C(H)—NR^(a)R^(b), where R^(a) andR^(b) independently represent C₁₋₆alkyl, e.g. to form a N,N-dimethylgroup. Such imidoformamides may be prepared by methods herein describedand may be removed under suitable acid conditions, such as at elevatedwith a suitable acid such as hydrochloric acid or para-toluenesulfonicacid in a solvent such as methanol or dioxane.

According to a first general method, a compound of formula (I), in whichR⁴ is H and R¹, R², R³ and R⁵ are as previously defined for formula (I),may be prepared from a compound of formula (II):

wherein R¹, R² and R⁵ are as previously defined for formula (I) bysulfonation by a suitable sulfonating agent, e.g. R³SO₂Cl or a sulfonicacid anhydride under standard conditions, e.g. in a suitable solvent,for example, dichloromethane, in the presence of base, typicallypyridine/4-dimethylaminopyridine mixtures, under an inert atmosphere.

Compounds of formula (I) where R⁴ is not hydrogen may be prepared fromcompounds of formula (I) where R⁴ is hydrogen by standard procedures.For example, a compound of formula (I) where R⁴ is R⁹SO₂— may beprepared by the addition of a suitable sulfonating agent, e.g. R⁹SO₂Cl,to a solution of a compound of formula (I) in an aprotic solvent, e.g.acetonitrile or dichloromethane, in the presence of base, e.g.,triethylamine, potassium carbonate or pyridine/4-dimethylaminopyridinemixtures.

Compounds of formula (II) may be bis-sulfonated in a one pot process,under well-known conditions, to form compounds of formula (I).

A compound of formula (I) where R⁴ and R³ are taken together with thenitrogen and sulphur atoms to which they are attached to form a 4 to7-membered monosulfonamide ring, may be prepared from a compound offormula (II), by the single step addition of a chloro-C₁₋₆alkylsulfonylchloride to a solution of a compound of formula (II) in a suitablesolvent, such as pyridine, allowing the reaction to progress thensubsequently adding a mild base, typically potassium carbonate in asuitable solvent, such as N,N-dimethylformamide and heating at elevatedtemperatures for several hours.

A compound of formula (I) where R⁴ is SO₂R⁹ and R⁹ and R³ are takentogether with the nitrogen and sulphur atoms to which they are attachedto form a 4 to 7-membered bis-sulfonamide ring, may be prepared from acompound of formula (II) by the two step addition of a C₁₋₆ alkylbis-sulfonyl chloride to a solution of a compound of formula (II) in asuitable solvent, such as pyridine, and heating at reflux for severalhours, typically overnight.

Compounds of formula (I) where R⁴ is an alkyl group may be prepared, forexample, by reaction of the compound of formula (I) with a suitablealkylating agent, e.g. R⁴—X, where X may be any leaving group, typicallyI, Br, Cl, OTs, OTf, O-mesylate, or O-trichloromethylsulphonate, in asuitable solvent, e.g. acetone, dichloromethane, acetonitrile,dimethylformamide or N-methylpyrrolidinone, in the presence of base,e.g. potassium carbonate, caesium carbonate, and sodium hydride. Othersalts may aid the reaction, for example, sodium iodide or potassiumiodide.

A compound of formula (I) in which R⁴ is an alkyl group, may be preparedby alkylation of a compound of formula (I) where R⁴ is hydrogen, usingsuitably acidic alcohol reagents via a Mitsunobu reaction.

A compound of formula (I) in which R⁴ is C₁₋₆ alkoxycarbonyl may beprepared by acylation of a compound of formula (I), where R⁴ is H, withan alkylhaloformate, e.g. a chloroformate, in a suitable solvent, suchas acetone at reflux temperature for several hours using a suitable basesuch as potassium carbonate.

Standard chemical procedures may be used to modify sidechains R², R³, R⁴and R⁵ of compounds of formula (I) provided that any reactive functionalgroups in the remaining sidechains are appropriately protected, ashereinbefore mentioned.

For example, a compound of formula (I) in which R² is CN may beconverted to a compound of formula (I) where R² is —C(O)N(R^(a))R^(b)and C₁₋₆ alkanoyl under standard conditions well-known to those skilledin the art.

Compounds of formula (I) where R⁴ is —(C₀₋₃alkylene)-cyclopropyl may beprepared from compounds of formula (I) where R⁴ is the correspondingalkenyl by standard cyclopropanation procedures, e.g. conversion of anethenyl derivative to the corresponding difluorocyclopropyl derivativeby heating a solution in a suitable solvent such as toluene with methylbenzoate at elevated temperature followed by addition oftrimethylsilyl-2,2-difluoro-2-(fluorosulfonyl)acetate dropwise overseveral hours. Such transformations are also described in WO98/24767.

Compounds of formula (I), where R⁴ is an C₂₋₆ alkenyl may be preparedfrom the corresponding bromoalkyl compound by dehydrobromination understandard conditions. Also, compounds of formula (I), where R⁴ is abromoalkyl group can also be used to prepare other compounds of formula(I) where the bromo-group is displaced with a suitable nucleophile e.g.a heteroaryl, in a suitable polar solvent, in the presence of a suitablebase.

Compounds of formula (I) where R⁴ is a readily oxidisable group, can beused to prepare alternative compounds of formula (I), e.g. conversion ofthioethers and hydroxyl substituted alkyl substituents to sulphones andcarbonyl derivatives respectively, using standard oxidising agents, suchas oxone or those described in “Handbook of Reagents for OrganicSynthesis—Oxidising and Reducing Agents” edited by S. D. Burke and R. L.Danheiser.

Compounds of formula (I) where R⁴ is an alkyl group containing analdehyde or ketone group can be prepared by oxidation of thecorresponding hydroxyalkyl group under standard conditions, such asDess-Martin periodinane in an aprotic solvent, such as dichloromethane.The resulting aldehyde or ketone groups can be further treated withnucleophilic reagents, in a suitable solvent, typically tetrahydrofuran,and optionally in the presence of a suitable catalyst, to give thenucleophilically substituted secondary or tertiary alcohol.

Additionally, compounds of formula (I) in which R⁴ is—(C₁₋₃alkylene)-CO₂H may be prepared by saponification of thecorresponding carboxylic acid ester.

A compound of formula (I) in which R⁵ is NH₂, may be used to prepare analternative compound of formula (I) by derivatisation of the aminogroup, including methods as discussed above for formation of R⁴ groups,e.g. alkylation or acylation. Additionally, a compound of formula (I)where R⁵ represents an optionally substituted C₁₋₆ alkylimino group, maybe prepared by heating the corresponding compound of formula (I) whereR⁵ represents NH₂ with an akdehyde, at elevated temperature, with asuitable catalyst, typically p-toluenesulfonic acid, with the optionaladdition of molecular sieves. A compound of formula (I) where R⁵represents an optionally substituted C₁₋₆ alkylimino group may be usedto form a different compound of formula (I) by reduction of the iminebond by a suitable reducing agent, for example, sodium borohydride, in asuitable solvent, typically ethanol.

Compounds of formula (I) where R⁵ is a derivatised amino group can befurther manipulated depending on the desired derivatisation. For exampleN-alkenyl derivatives may be oxidatively cleaved to produce aldehydesunder standard conditions. Such aldehyde derivatives may be furthermanipulated to give other derivatives, e.g. reductive amination understandard conditions to give secondary and tertiary amines.

Also, reaction of compounds of formula (I) in which R⁵ is NH₂, with anacid chloride or an acid anhydride in an aprotic solvent, such asacetonitrile at reflux overnight, produces a compound of formula (I) inwhich R⁵ is —NHR¹³ and R¹³ represents an optionally substituted C₁₋₆alkanoyl or C₁₋₆ alkoxycarbonyl group. Alternatively, the reaction maytake place coupling a carboxylic acid with an amine in the presence of asuitable coupling agent such as a water-soluble carbodiimide.

A compound of formula (I) in which R⁵ is NH₂, can undergo reaction witha tri-alkyl orthoformate, e.g. triethyl orthoformate, in acidicconditions, by heating at elevated temperatures, typically 60° C., forseveral hours, typically 2 to 4 hours, to give compounds of formula (I)in which R⁵ is a methylimino group, substituted by an optionallysubstituted C₁₋₆ alkoxy group, e.g. ethoxy. These imino-ethers can berefluxed with primary or secondary amines optionally in a suitablesolvent to give other compounds of formula (I) wherein R⁵ is amethylimino group, substituted by a di-C₁₋₆ alkyl amino group, e.g.dimethylamino.

A compound of formula (I) in which R⁵ is H, may be prepared by thediazotisation of a compound of formula (I) in which R⁵ is NH₂ by avariety of standard diazotisation procedures.

Compounds of formula (I) in which R⁵ is NH₂, can be converted to give acompound of formula (I) wherein R⁵ is halo, utilising standard Sandmeyerreaction conditions.

Compounds of formula (I) in which R⁵ is NH₂ can also be converted tocarbamates or ureas under standard conditions. Halo-substitutedcarbamates may be further reacted with nucleophiles such as primary orsecondary amines in a suitable alcoholic solvent, optionally with theaddition of lithium iodide and allowing to stir at room temperature forseveral hours, to give the nucleophilically substituted product e.g. asecondary or tertiary amine substituted derivative.

A compound of formula (II) may be prepared as shown in Scheme 1 below,wherein R¹, R² and R⁵ are as previously defined, the —CO₂ Me group isillustrative of any carboxylic acid ester group and the—CO₂(CH₂)₂Si(CH₃)₂ is illustrative of any suitable amino protectinggroup resulting from the Curtius rearrangement.

A compound of formula (IV) may be obtained from a compound of formula(III) by conventional halogenation procedures, e.g. treatment ofN-iodosuccinimide in a suitable solvent such as acetonitrile to give theiodo compound. A compound of formula (IV) may be carbonylated usingconventional procedures to give a compound of formula (V), e.g., using apalladium catalyst. Saponification of the methyl ester, of formula (V),to give the acid, of formula (VI), may be achieved using standard esterhydrolysis conditions. A compound of formula (VII) may be prepared froma compound of formula (VI) by the Curtius rearrangement of the acylazide prepared in situ by conventional procedures, e.g.,diphenylphosphoryl azide is added dropwise to a solution of a compoundof formula (VI), triethylamine and 2-(trimethylsilyl)ethanol in1,4-dioxane at elevated temperature. Deprotection to yield the amine offormula (II) may be effected using a variety of fluoride induceddesilylation procedures, such as heating a solution of a compound offormula (VII) and tetrabutylammonium fluoride in a suitable solvent,typically tetrahydrofuran, at elevated temperatures.

An alternative route to compounds of formula (II) is via nitration ofcompounds of formula (III) to give nitro compounds of formula (VIII)followed by reduction of the nitro substituent of compounds of formula(VIII) to the amines of formula (II) as shown in Scheme 2, wherein R¹,R² and R⁵ are as previously defined for compounds of formula (I).

The preparation of compounds of formula (VIII), wherein R¹, R² and R⁵are as previously defined for formula (I), may be effected byconventional electrophilic nitration procedures, then reduction ofcompounds of formula (VIII) may be facilitated by a variety of reducingagents including those described in “Handbook of Reagents for OrganicSynthesis—Oxidising and Reducing Agents” edited by S. D. Burke and R. L.Danheiser.

Compounds of formula (III) and (VIII) are useful compounds to undergofunctional group interconversion at, for example, position R⁵ to givedifferent groups of formula (VIII) using transformations hereindescribed and obvious to those skilled in the art.

The preparation of a compound of formula (III) may be achieved by thereduction of a compound of formula (IV), wherein halo is iodo, e.g. bytransmetallation with a suitable organometallic reagent such as aGrignard reagent, typically isopropylmagnesium chloride, in a suitablesolvent such as tetrahydrofuran at reduced temperature, under suitableaqueous work-up conditions.

Synthesis of the arylpyrazole template can be readily performed.

A compound of formula (III) wherein R² is C₁₋₆ alkyl optionallysubstituted by halo or C₃₋₈ cycloalkyl may be prepared from a hydrazineof formula (IX) by reaction with a α-cyanoketone of formula (X)

wherein R² represents C₁₋₆ alkyl optionally substituted by halo or C₃₋₈cycloalkyl, at elevated temperatures. Compounds of formula (X) arewell-known or can be prepared by methods well-known to those skilled inthe art.

A compound of formula (IX) may be prepared by diazotisation of acompound of formula (XI), by reaction with sodium nitrite in an acidicmixture, for example glacial acetic acid and sulphuric acid attemperatures between 5-60° C. to give the diazonium salt of formula(XII)

followed by reduction of the diazonium salt of formula (XII) with anagent such as stannous chloride in a concentrated acid such ashydrochloric acid.

Alternatively, a compound of formula (XIII)

where R² represents an optionally substituted C₁₋₆alkyl and the methylgroup is illustrative of any suitable carboxylic ester protecting group,may be prepared from a hydrazine of formula (IX) and a compound offormula (XIV)

wherein L is a leaving group, typically Cl, in a suitable solvent,typically diethyl ether, and a suitable base such as potassiumcarbonate.

A compound of formula (III), wherein R² is hydrogen, C₁₋₆ alkyloptionally substituted by halo or C₃₋₈ cycloalkyl, may be prepared byreaction of a compound of formula (IX) with a compound of formula (XV),

wherein R² is hydrogen, C₁₋₆ alkyl optionally substituted by halo orC₃₋₈ cycloalkyl, and L is a leaving group such as chloro, bromo, iodo,at elevated temperatures.

A compound of formula (V) where R² represents C₁₋₆ alkyl, C₁₋₆haloalkyl,C₃₋₈ cycloalkyl or cyano may be prepared by reaction of a compound offormula (IX) with a compound of formula (XVI)

wherein R² represents C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl orcyano, in aprotic solvents such as diethyl ether in the presence of amild base such as potassium carbonate.

Chloroalkenes of formula (XVI) are obtained by chlorination of alkenesof formula (XVII) using phosphorous pentachloride in a solvent such asdichloromethane at room temperature.

Functionalised alkenes of formula (XVII) may be synthesised using a widevariety of literature methodology.

Alternatively, compounds of formula (III), where R² represents CN and R⁵represents OH or NH₂ can be synthesised via the Japp-Klingemannreaction: the reaction of aryl diazonium salts of formula (IX) withcompounds of formula (XVIII) or (XIX), wherein R and R″ are alkylgroups.

The diazonium salts of formula (IX) are typically generated in situ, forexample by the dropwise addition of a solution of the aminobenzenes offormula (VIII) in glacial acetic acid to a solution of sodium nitrite inconcentrated sulphuric/glacial acetic acid mixtures at reducedtemperature, typically 10° C., followed by heating at 50° C. for severalhours, typically 1 hour and allowing to cool to room temperature. Thissolution of the diazonium salt is then added dropwise to a solution of acompound of formula (XVIII) or (XIX) in a suitable solvent, such asacetic acid followed by stirring at room temperature for up to 1 hour.The reaction mixture is poured into water and extracted with a waterimmiscible organic solvent such as dichloromethane. Aqueous ammoniumhydroxide is added to the organic extract and stirred overnight to givecompounds of formula (III).

Compounds of formula (XIX) can be prepared by the addition ofglycolonitrile to alpha-nitrile esters in a suitable solvent, in thepresence of a mild base, typically, potassium carbonate, and stirred forseveral hours at room temperature.

An arylpyrazole compound of formula (XX),

where R¹ is previously defined and the methyl group is illustrative ofany carboxylic acid protecting group, may be prepared by reaction of ahydrazine of formula (IX) with an electrophile such as a compound offormula (XXI)

in an aprotic solvent, such as isopropyl alcohol, at reflux for severalhours.

The synthesis of the desired 1-aminobenzenes can be achieved usingstandard conditions. For example, 2,6-unsubstituted aniline derivativescan be mono- or di-chlorinated by the addition of N-chlorosuccinimide ina suitable solvent, such as acetonitrile, and heating at elevatedtemperatures, typically 45-50° C., for several hours, typically from 1to 3 hours.

Moreover, persons skilled in the art will be aware of variations of, andalternatives to, the processes described which allow the compoundsdefined by formula (I) to be obtained.

It will also be appreciated by persons skilled in the art that, withincertain of the processes described, the order of the synthetic stepsemployed may be varied and will depend inter alia on factors such as thenature of other functional groups present in a particular substrate, theavailability of key intermediates, and the protecting group strategy (ifany) to be adopted. Clearly, such factors will also influence the choiceof reagent for use in the said synthetic steps. It will also beappreciated that various standard substituent or functional groupinterconversions and transformations within certain compounds of formula(I) will provide other compounds of formula (I).

The skilled person will appreciate that the compounds of the inventioncould be made by methods other than those herein described, byadaptation of the methods herein described and/or adaptation of methodsknown in the art, for example the art described herein, or usingstandard textbooks such as “Comprehensive Organic Transformations—AGuide to Functional Group Transformations”, R C Larock, Wiley-VCH (1999or later editions), “March's Advanced Organic Chemistry—Reactions,Mechanisms and Structure”, M B Smith, J. March, Wiley, (5th edition orlater) “Advanced Organic Chemistry, Part B, Reactions and Synthesis”, FA Carey, R J Sundberg, Kluwer Academic/Plenum Publications, (2001 orlater editions), “Organic Synthesis—The Disconnection Approach”, SWarren (Wiley), (1982 or later editions), “Designing Organic Syntheses”S Warren (Wiley) (1983 or later editions), “Guidebook To OrganicSynthesis” R K Mackie and DM Smith (Longman) (1982 or later editions),etc., and the references therein as a guide.

It is to be understood that the synthetic transformation methodsmentioned herein are exemplary only and they may be carried out invarious different sequences in order that the desired compounds can beefficiently assembled. The skilled chemist will exercise his judgementand skill as to the most efficient sequence of reactions for synthesisof a given target compound. For example, substituents may be added toand/or chemical transformations performed upon, different intermediatesto those mentioned hereinafter in conjunction with a particularreaction. This will depend inter alia on factors such as the nature ofother functional groups present in a particular substrate, theavailability of key intermediates and the protecting group strategy (ifany) to be adopted. Clearly, the type of chemistry involved willinfluence the choice of reagent that is used in the said syntheticsteps, the need, and type, of protecting groups that are employed, andthe sequence for accomplishing the synthesis. The procedures may beadapted as appropriate to the reactants, reagents and other reactionparameters in a manner that will be evident to the skilled person byreference to standard textbooks and to the examples providedhereinafter.

It will be apparent to those skilled in the art that sensitivefunctional groups may need to be protected and deprotected duringsynthesis of a compound of the invention. This may be achieved byconventional methods, for example as described in “Protective Groups inOrganic Synthesis” by T W Greene and P G M Wuts, John Wiley & Sons Inc(1999), and references therein.

Pharmaceutically acceptable salts of the compounds of formula (I)include the acid addition and base salts thereof for compounds ofsufficient acidity or basisity.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate,succinate, tartrate, tosylate and trifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts.

For a review on suitable salts, see “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

A pharmaceutically acceptable salt of a compound of formula (I) may bereadily prepared by mixing together solutions of the compound of formula(I) and the desired acid or base, as appropriate. The salt mayprecipitate from solution and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionisation in thesalt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm ‘hydrate’ is employed when said solvent is water.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionised, partially ionised, or non-ionised. For a review of suchcomplexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August1975).

Hereinafter all references to compounds of formula (I) includereferences to salts, solvates and complexes thereof and to solvates andcomplexes of salts thereof.

The compounds of the invention include compounds of formula (I) ashereinbefore defined, and all polymorphs and prodrugs thereof. Theinvention also includes all isomers of the compounds of formula (I)(including optical, geometric and tautomeric isomers) as hereinafterdefined and isotopically-labeled compounds of formula (I).

Within the scope of the invention are so-called ‘prodrugs’ of thecompounds of formula (I). Thus certain derivatives of compounds offormula (I) which may have little or no pharmacological activitythemselves can, when administered into or onto the body, be convertedinto compounds of formula (I) having the desired activity, for example,by hydrolytic cleavage. Such derivatives are referred to as ‘prodrugs’.It will be appreciated that certain compounds of formula (I) maythemselves act as prod-drugs of other compounds of formula (I). Furtherinformation on the use of prodrugs may be found in ‘Pro-drugs as NovelDelivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella)and ‘Bioreversible Carriers in Drug Design’, Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be producedby replacing the 5-amino substituent on the pyrazole ring in thecompounds of formula (I) with certain moieties known to those skilled inthe art as ‘pro-drug moieties’ as described, for example, in “Design ofProdrugs” by H Bundgaard (Elsevier, 1985); “Design and application ofprodrugs,” Textbook of Drug Design and Discovery, (3^(rd) Edition),2002, 410-458, (Taylor and Francis Ltd., London); and referencestherein.

Suitable prodrugs may have an N-containing group at the 5-position ofthe pyrazole ring of formula (I) and are bound to the ring through N.The 5-N group can be substituted once or twice. Examples of substituentsinclude: alkyl amines, aryl amines, amides, ureas, carbamates, cycliccarbamates, imines, enamines, imides, cyclic imides, sulfenamides, andsulfonamides. The hydrocarbon portion of these groups contain C₁₋₆alkyl, phenyl, heteroaryl such as pyridyl, C₂₋₆ alkenyl, and C₃₋₈cycloalkyl; wherein each of the above groups may include one or moreoptional substituents where chemically possible independently selectedfrom: halo; hydroxy; C₁₋₆ alkyl and C₁₋₆ alkoxy.

Further examples of replacement groups in accordance with the foregoingexample and examples of other prodrug types may be found in theaforementioned references.

A prodrug according to the invention can be readily identified byadministering it to a test animal and sampling a body fluid for acompound of formula (I).

Compounds of formula (I) containing one or more asymmetric carbon atomscan exist as two or more stereoisomers. Where a compound of formula (I)contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E)isomers are possible. Where the compound contains, for example, a ketoor oxime group or an aromatic moiety, tautomeric isomerism('tautomerism') can occur. It follows that a single compound may exhibitmore than one type of isomerism.

Included within the scope of the present invention are allstereoisomers, geometric isomers and tautomeric forms of the compoundsof formula (I), including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidaddition or base salts wherein the counterion is optically active, forexample, D-lactate or L-lysine, or racemic, for example, DL-tartrate orDL-arginine.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallisation.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of formula (I) contains an acidic or basicmoiety, an acid or base such as tartaric acid or 1-phenylethylamine. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50%isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine,typically 0.1% diethylamine. Concentration of the eluate affords theenriched mixture.

Stereoisomeric conglomerates may be separated by conventional techniquesknown to those skilled in the art—see, for example, “Stereochemistry ofOrganic Compounds” by E L Eliel (Wiley, New York, 1994).

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of formula (I) wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number usuallyfound in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁸Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Certain isotopically-labelled compounds of formula (I), for example,those incorporating a radioactive isotope, are useful in drug and/orsubstrate tissue distribution studies. The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for thispurpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof formula (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the accompanying Examples and Preparations using anappropriate isotopically-labeled reagents in place of the non-labeledreagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO. Compounds of the inventionintended for pharmaceutical use may be administered as crystalline oramorphous products. They may be obtained, for example, as solid plugs,powders, or films by methods such as precipitation, crystallization,freeze drying, spray drying, or evaporative drying. Microwave or radiofrequency drying may be used for this purpose.

They may be administered alone or in combination with one or more othercompounds of the invention or in combination with one or more otherdrugs (or as any combination thereof).

Compounds of this invention can also be mixed with one or morebiologically active compounds or agents including insecticides,acaricides, anthelmintics, fungicides, nematocides, antiprotozoals,bactericides, growth regulators, entomopathogenic bacteria, viruses orfungi to form a multi-component pesticide giving an even broaderspectrum of pharmaceutical, veterinary or agricultural utility. Thus thepresent invention also pertains to a composition comprising abiologically effective amount of compounds of the invention and aneffective amount of at least one additional biologically active compoundor agent and can further comprise one or more of surfactant, a soliddiluent or a liquid diluent.

The following list of biologically active compounds together with whichthe compounds of the invention can be used is intended to illustrate thepossible combinations, but not to impose any limitation.

For example, compounds of the present invention may be co-administeredor used in combination with anthelmintic agents. Such anthelminticagents include, compounds selected from the macrocyclic lactone class ofcompounds such as ivermectin, avermectin, abamectin, emamectin,eprinomectin, doramectin, selamectin, moxidectin, nemadectin andmilbemycin derivatives as described in EP-357460, EP-444964 andEP-594291. Additional anthelmintic agents include semisynthetic andbiosynthetic avermectin/milbemycin derivatives such as those describedin U.S. Pat. No. 5,015,630, WO-9415944 and WO-9522552. Additionalanthelmintic agents include the benzimidazoles such as albendazole,cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole,oxibendazole, parbendazole, and other members of the class. Additionalanthelmintic agents include imidazothiazoles and tetrahydropyrimidinessuch as tetramisole, levamisole, pyrantel pamoate, oxantel or morantel.

Compounds of this invention may also be used in combination withderivatives and analogues of the paraherquamide/marcfortine class ofanthelmintic agents, as well as the antiparasitic oxazolines such asthose disclosed in U.S. Pat. No. 5,478,855, U.S. Pat. No. 4,639,771 andDE-19520936.

Compounds of this invention may be co-administered or used incombination with derivatives and analogues of the general class ofdioxomorpholine antiparasitic agents as described in WO-9615121 and alsowith anthelmintic active cyclic depsipeptides such as those described inWO-9611945, WO-9319053, WO-9325543, EP-626375, EP-382173, WO-9419334,EP-382173, and EP-503538.

Compounds of this invention may be co-administered or used incombination with other ectoparasiticides; for example, fipronil;pyrethroids; organophosphates; insect growth regulators such aslufenuron; ecdysone agonists such as tebufenozide and the like;neonicotinoids such as imidacloprid and the like.

Other examples of such biologically active compounds include but are notrestricted to the following:

Organophosphates: acephate, azamethiphos, azinphos-ethyl,azinphos-methyl, bromophos, bromophos-ethyl, cadusafos, chlorethoxyphos,chlorpyrifos, chlorfenvinphos, chlormephos, demeton, demeton-5-methyl,demeton-5-methyl sulphone, dialifos, diazinon, dichlorvos, dicrotophos,dimethoate, disulfoton, ethion, ethoprophos, etrimfos, famphur,fenamiphos, fenitrothion, fensulfothion, fenthion, flupyrazofos,fonofos, formothion, fosthiazate, heptenophos, isazophos, isothioate,isoxathion, malathion, methacriphos, methamidophos, methidathion,methyl-parathion, mevinphos, monocrotophos, naled, omethoate,oxydemeton-methyl, paraoxon, parathion, parathion-methyl, phenthoate,phosalone, phosfolan, phosphocarb, phosmet, phosphamidon, phorate,phoxim, pirimiphos, pirimiphos-methyl, profenofos, propaphos,proetamphos, prothiofos, pyraclofos, pyridapenthion, quinaiphos,sulprophos, temephos, terbufos, tebupirimfos, tetrachlorvinphos,thimeton, triazophos, trichlorfon, vamidothion.

Carbamates: alanycarb, aldicarb, 2-sec-butylphenyl methylcarbamate,benfuracarb, carbaryl, carbofuran, carbosulfan, cloethocarb,ethiofencarb, fenoxycarb, fenthiocarb, furathiocarb, HCN-801,isoprocarb, indoxacarb, methiocarb, methomyl,5-methyl-m-cumenylbutyryl(methyl)carbamate, oxamyl, pirimicarb,propoxur, thiodicarb, thiofanox, triazamate, UC-51717

Pyrethroids: acrinathin, allethrin, alphametrin, 5-benzyl-3-furylmethyl(E)-(1R)-cis-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropanecarboxylate,bifenthrin, β-cyfluthrin, cyfluthrin, α-cypermethrin, β-cypermethrin,bioallethrin, bioallethrin((S)-cyclopentylisomer), bioresmethrin,bifenthrin, NCI-85193, cycloprothrin, cyhalothrin, cythithrin,cyphenothrin, deltamethrin, empenthrin, esfenvalerate, ethofenprox,fenfluthrin, fenpropathrin, fenvalerate, flucythrinate, flumethrin,fluvalinate (D isomer), imiprothrin, cyhalothrin, X-cyhalothrin,permethrin, phenothrin, prallethrin, pyrethrins (natural products),resmethrin, tetramethrin, transfluthrin, theta-cypermethrin,silafluofen, t-fluvalinate, tefluthrin, tralomethrin, Zeta-cypermethrin.

Arthropod growth regulators: a) chitin synthesis inhibitors:benzoylureas: chlorfluazuron, diflubenzuron, fluazuron, flucycloxuron,flufenoxuron, hexaflumuron, lufenuron, novaluron, teflubenzuron,triflumuron, buprofezin, diofenolan, hexythiazox, etoxazole,chlorfentazine; b) ecdysone antagonists: halofenozide, methoxyfenozide,tebufenozide; c) juvenoids: pyriproxyfen, methoprene, fenoxycarb; d)lipid biosynthesis inhibitors: spirodiclofen

Other antiparasitics: acequinocyl, amitraz, AKD-1022, ANS-118,azadirachtin, Bacillus thuringiensis, bensultap, bifenazate, binapacryl,bromopropylate, BTG-504, BTG-505, camphechlor, cartap, chlorobenzilate,chlordimeform, chlorfenapyr, chromafenozide, clothianidine, cyromazine,diacloden, diafenthiuron, DBI-3204, dinactin,dihydroxymethyldihydroxypyrrolidine, dinobuton, dinocap, endosulfan,ethiprole, ethofenprox, fenazaquin, flumite, MTI-800, fenpyroximate,fluacrypyrim, flubenzimine, flubrocythrinate, flufenzine, flufenprox,fluproxyfen, halofenprox, hydramethylnon, IKI-220, kanemite, NC-196,neem guard, nidinorterfuran, nitenpyram, SD-35651, WL-108477, pirydaryl,propargite, protrifenbute, pymethrozine, pyridaben, pyrimidifen,NC-1111, R-195, RH-0345, RH-2485, RYI-210, S-1283, S-1833, SI-8601,silafluofen, silomadine, spinosad, tebufenpyrad, tetradifon,tetranactin, thiacloprid, thiocyclam, thiamethoxam, tolfenpyrad,triazamate, triethoxyspinosyn, trinactin, verbutin, vertalec, yl-5301

Fungicides: acibenzolar, aldimorph, ampropylfos, andoprim, azaconazole,azoxystrobin, benalaxyl, benomyl, bialaphos, blasticidin-S, Bordeauxmixture, bromuconazole, bupirimate, carpropamid, captafol, captan,carbendazim, chlorfenazole, chloroneb, chloropicrin, chlorothalonil,chlozolinate, copper oxychloride, copper salts, cyflufenamid, cymoxanil,cyproconazole, cyprodinil, cyprofuram, RH-7281, diclocymet,diclobutrazole, diclomezine, dicloran, difenoconazole, RP-407213,dimethomorph, domoxystrobin, diniconazole, diniconazole-M, dodine,edifenphos, epoxiconazole, famoxadone, fenamidone, fenarimol,fenbuconazole, fencaramid, fenpiclonil, fenpropidin, fenpropimorph,fentin acetate, fluazinam, fludioxonil, flumetover, flumorf/flumorlin,fentin hydroxide, fluoxastrobin, fluquinconazole, flusilazole,flutolanil, flutriafol, folpet, fosetyl-aluminium, furalaxyl,furametapyr, hexaconazole, ipconazole, iprobenfos, iprodione,isoprothiolane, kasugamycin, krsoxim-methyl, mancozeb, maneb, mefenoxam,mepronil, metalaxyl, metconazole, metominostrobin/fenominostrobin,metrafenone, myclobutanil, neo-asozin, nicobifen, orysastrobin,oxadixyl, penconazole, pencycuron, probenazole, prochloraz, propamocarb,propioconazole, proquinazid, prothioconazole, pyrifenox, pyraclostrobin,pyrimethanil, pyroquilon, quinoxyfen, spiroxamine, sulfur, tebuconazole,tetrconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram,tiadinil, triadimefon, triadimenol, tricyclazole, trifloxystrobin,triticonazole, validamycin, vinclozin

Biological agents: Bacillus thuringiensis ssp aizawai, kurstaki,Bacillus thuringiensis delta endotoxin, baculovirus, entomopathogenicbacteria, virus and fungi

Bactericides: chlortetracycline, oxytetracycline, streptomycin,

Generally, they will be administered as a formulation in associationwith one or more pharmaceutically acceptable excipients. The term“excipient” is used herein to describe any ingredient other than thecompound(s) of the invention. The choice of excipient will to a largeextent depend on factors such as the particular mode of administration,the effect of the excipient on solubility and stability, and the natureof the dosage form. The compounds of the invention are of particularvalue in the control of parasites which are injurious to, or spread oract as vectors of diseases in, man and domestic animals, for examplethose hereinbefore mentioned, and more especially in the control ofticks, mites, lice, fleas, midges and biting, nuisance and myiasisflies. They are particularly useful in controlling arthropods which arepresent inside domestic host animals or which feed in or on the skin orsuck the blood of the animal, for which purpose they may be administeredorally, parenterally, percutaneously or topically.

Pharmaceutical compositions suitable for the delivery of compounds ofthe present invention and methods for their preparation will be readilyapparent to those skilled in the art. Such compositions and methods fortheir preparation may be found, for example, in ‘Remington'sPharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995).

With respect to their use in mammals, the compounds may be administeredalone or in a formulation appropriate to the specific use envisaged, theparticular species of host mammal being treated and the parasiteinvolved.

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed by which the compound enters the blood stream directly from themouth.

Formulations suitable for oral administration include solid formulationssuch as tablets, capsules containing particulates, liquids, or powders,lozenges (including liquid-filled), chews, multi- and nano-particulates,gels, solid solution, liposome, films (including muco-adhesive), ovules,sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations may be employed as fillers in soft or hard capsulesand typically comprise a carrier, for example, water, ethanol,polyethylene glycol, propylene glycol, methylcellulose, or a suitableoil, and one or more emulsifying agents and/or suspending agents. Liquidformulations may also be prepared by the reconstitution of a solid, forexample, from a sachet.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in ExpertOpinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen(2001).

For tablet dosage forms, depending on dose, the drug may make up from 1wt % to 80 wt % of the dosage form, more typically from 5 wt % to 60 wt% of the dosage form. In addition to the drug, tablets generally containa disintegrant. Examples of disintegrants include sodium starchglycolate, sodium carboxymethyl cellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone,methyl cellulose, microcrystalline cellulose, lower alkyl-substitutedhydroxypropyl cellulose, starch, pregelatinised starch and sodiumalginate. Generally, the disintegrant will comprise from 1 wt % to 25 wt%, preferably from 5 wt % to 20 wt % of the dosage form.

Binders are generally used to impart cohesive qualities to a tabletformulation. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose andhydroxypropyl methylcellulose. Tablets may also contain diluents, suchas lactose (monohydrate, spray-dried monohydrate, anhydrous and thelike), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such assodium lauryl sulfate and polysorbate 80, and glidants such as silicondioxide and talc. When present, surface active agents may comprise from0.2 wt % to 5 wt % of the tablet, and glidants may comprise from 0.2 wt% to 1 wt % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate,calcium stearate, zinc stearate, sodium stearyl fumarate, and mixturesof magnesium stearate with sodium lauryl sulphate. Lubricants generallycomprise from 0.25 wt % to 10 wt %, preferably from 0.5 wt % to 3 wt %of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouringagents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 wt % toabout 90 wt % binder, from about 0 wt % to about 85 wt % diluent, fromabout 2 wt % to about 10 wt % disintegrant, and from about 0.25 wt % toabout 10 wt % lubricant.

Tablet blends may be compressed directly or by roller to form tablets.Tablet blends or portions of blends may alternatively be wet-, dry-, ormelt-granulated, melt congealed, or extruded before tabletting. Thefinal formulation may comprise one or more layers and may be coated oruncoated; it may even be encapsulated.

The formulation of tablets is discussed in “Pharmaceutical Dosage Forms:Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y.,N.Y., 1980 (ISBN 0-8247-6918-X).

Solid formulations for oral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Suitable modified release formulations for the purposes of the inventionare described in U.S. Pat. No. 6,106,864. Details of other suitablerelease technologies such as high energy dispersions and osmotic andcoated particles are to be found in Verma et al, PharmaceuticalTechnology On-line, 25(2), 1-14 (2001).

The compounds of the invention may also be administered directly intothe blood stream, into muscle, or into an internal organ. Suitable meansfor parenteral administration include bolus, intravenous, intraarterial,intraperitoneal, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular and subcutaneous. Suitabledevices for parenteral administration include needle (includingmicroneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which maycontain excipients such as salts, carbohydrates and buffering agents(preferably to a pH of from 3 to 9), but, for some applications, theymay be more suitably formulated as a sterile non-aqueous solution or asa dried form to be used in conjunction with a suitable vehicle such assterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, forexample, by lyophilisation, may readily be accomplished using standardpharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (I) used in the preparation ofparenteral solutions may be increased by the use of appropriateformulation techniques, such as the incorporation ofsolubility-enhancing agents.

Formulations for parenteral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease. Thus compounds of the invention may be formulated as a solid,semi-solid, or thixotropic liquid for administration as an implanteddepot providing modified release of the active compound. Examples ofsuch formulations include drug-coated stents and PGLA microspheres.

The compounds of the invention may also be administered topically to theskin or mucosa, that is, dermally or transdermally. Typical formulationsfor this purpose include drenches, gels, hydrogels, lotions, solutions,creams, ointments, dusting powders, dressings, foams, films, skinpatches, wafers, implants, sponges, fibres, bandages and microemulsions.Liposomes may also be used. Typical carriers include alcohol, water,mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethyleneglycol and propylene glycol. Penetration enhancers may beincorporated—see, for example, J Pharm Sci, 88 (10), 955-958 by Finninand Morgan (October 1999). Pour-on or spot-on formulations may beprepared by dissolving the active ingredient in an acceptable liquidcarrier vehicle such as butyl digol, liquid paraffin or a non-volatileester, optionally with the addition of a volatile component such aspropan-2-ol. Alternatively, pour-on, spot-on or spray formulations canbe prepared by encapsulation, to leave a residue of active agent on thesurface of the animal. Injectable formulations may be prepared in theform of a sterile solution which may contain other substances, forexample enough salts or glucose to make the solution isotonic withblood.

Other means of topical administration include delivery byelectroporation, iontophoresis, phonophoresis, sonophoresis andmicroneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

Formulations for topical administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

The compounds of the invention can also be administered intranasally orby inhalation, typically in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurised container, pump, spray, atomiser (preferably anatomiser using electrohydrodynamics to produce a fine mist), ornebuliser, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser containsa solution or suspension of the compound(s) of the invention comprising,for example, ethanol, aqueous ethanol, or a suitable alternative agentfor dispersing, solubilising, or extending release of the active, apropellant(s) as solvent and an optional surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug productis micronised to a size suitable for delivery by inhalation (typicallyless than 5 microns). This may be achieved by any appropriatecomminuting method, such as spiral jet milling, fluid bed jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenisation, or spray drying.

Capsules (made, for example, from gelatin or HPMC), blisters andcartridges for use in an inhaler or insufflator may be formulated tocontain a powder mix of the compound of the invention, a suitable powderbase such as lactose or starch and a performance modifier such asl-leucine, mannitol, or magnesium stearate. The lactose may be anhydrousor in the form of the monohydrate, preferably the latter. Other suitableexcipients include dextran, glucose, maltose, sorbitol, xylitol,fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomiser usingelectrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of the compound of the invention per actuation and the actuationvolume may vary from 1 μl to 100 μl. A typical formulation may comprisea compound of formula (I), propylene glycol, sterile water, ethanol andsodium chloride. Alternative solvents which may be used instead ofpropylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, suchas saccharin or saccharin sodium, may be added to those formulations ofthe invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated tobe immediate and/or modified release using, for example,poly(DL-lactic-coglycolic acid (PGLA). Modified release formulationsinclude delayed-, sustained-, pulsed-, controlled-, targeted andprogrammed release.

In the case of dry powder inhalers and aerosols, the dosage unit isdetermined by means of a valve which delivers a metered amount. Units inaccordance with the invention are typically arranged to administer ametered dose or “puff” containing from 1 to 1000 μg of the compound offormula (I). The overall daily dose will typically be in the range 100μg to 100 mg which may be administered in a single dose or, moreusually, as divided doses throughout the day.

The compounds of the invention may be administered rectally orvaginally, for example, in the form of a suppository, pessary, or enema.Cocoa butter is a traditional suppository base, but various alternativesmay be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

The compounds of the invention may also be administered directly to theeye or ear, typically in the form of drops of a micronised suspension orsolution in isotonic, pH-adjusted, sterile saline. Other formulationssuitable for ocular and aural administration include ointments,biodegradable (e.g. absorbable gel sponges, collagen) andnon-biodegradable (e.g. silicone) implants, wafers, lenses andparticulate or vesicular systems, such as niosomes or liposomes. Apolymer such as crossed-linked polyacrylic acid, polyvinylalcohol,hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum,may be incorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular/aural administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted, or programmedrelease.

The compounds of the invention may be combined with solublemacromolecular entities, such as cyclodextrin and suitable derivativesthereof or polyethylene glycol-containing polymers, in order to improvetheir solubility, dissolution rate, taste-masking, bioavailabilityand/or stability for use in any of the aforementioned modes ofadministration.

Drug-cyclodextrin complexes, for example, are found to be generallyuseful for most dosage forms and administration routes. Both inclusionand non-inclusion complexes may be used. As an alternative to directcomplexation with the drug, the cyclodextrin may be used as an auxiliaryadditive, i.e. as a carrier, diluent, or solubiliser. Most commonly usedfor these purposes are alpha-, beta- and gamma-cyclodextrins, examplesof which may be found in International Patent Applications Nos. WO91/11172, WO 94/02518 and WO 98/55148.

Acceptable liquid carriers include vegetable oils such as sesame oil,glycerides such as triacetin, esters such as benzyl benzoate, isopropylmyristate and fatty acid derivatives of propylene glycol, as well asorganic solvents such as pyrrolidin-2-one and glycerol formal. Theformulations are prepared by dissolving or suspending the activeingredient in the liquid carrier such that the final formulationcontains from 0.01 to 10% by weight of the active ingredient.

Such formulations are prepared in a conventional manner in accordancewith standard medicinal or veterinary practice.

These formulations will vary with regard to the weight of activecompound contained therein, depending on the species of host animal tobe treated, the severity and type of infection and the body weight ofthe host. For parenteral, topical and oral administration, typical doseranges of the active ingredient are 0.01 to 100 mg per kg of body weightof the animal. Preferably the range is 0.1 to 10 mg per kg.

As an alternative the compounds may be administered to a non-humananimal with the drinking water or feedstuff and for this purpose aconcentrated feed additive or premix may be prepared for mixing with thenormal animal feed or drink.

Inasmuch as it may desirable to administer a combination of activecompounds, for example, for the purpose of treating a particular diseaseor condition, it is within the scope of the present invention that twoor more pharmaceutical compositions, at least one of which contains acompound in accordance with the invention, may conveniently be combinedin the form of a kit suitable for coadministration of the compositions.

Thus the kit of the invention comprises two or more separatepharmaceutical compositions, at least one of which contains a compoundof formula (I) in accordance with the invention, and means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is the familiarblister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administeringdifferent dosage forms, for example, oral and parenteral, foradministering the separate compositions at different dosage intervals,or for titrating the separate compositions against one another. Toassist compliance, the kit typically comprises directions foradministration and may be provided with a so-called memory aid.

For administration to animal patients, the total daily dose of thecompounds of the invention is typically in the range 0.1 mg/kg to 100mg/kg depending, of course, on the mode of administration. For example,oral administration may require a total daily dose of from 0.5 mg/kg to100 mg/kg, while an intravenous dose may only require from 0.1 mg/kg to10 mg/kg. The total daily dose may be administered in single or divideddoses.

The veterinarian will readily be able to determine doses for individualanimals according to age, weight and need.

The compounds of the invention also have utility in the control of plantpests, soil inhabiting pests and other environmental pests.

Compositions suitable for applications in agriculture, horticultureinclude formulations suitable for use as, for example, sprays, dusts,granules, fogs, foams, emulsions. The active compound is generallyapplied to the locus in which arthropod or nematode infestation is to becontrolled at a rate of about 0.02 kg to about 20 kg of active compoundper hectare of locus treated. Adverse weather conditions, pestresistance and other factors may require that the active ingredient beused in higher proportions. For foliar application, a rate of 0.01 to 1kg/ha may be used.

The compounds of the invention may also be applied in solid or liquidcompositions to the soil principally to control those nematodes dwellingtherein but also to the foliage principally to control those nematodesattacking the aerial parts of the plants. The active component can bewashed into the soil by spraying with water or by the natural action ofrainfall. During or after application, the formulation can, if desired,be distributed mechanically in the soil.

Application can be prior to planting, at planting, after planting butbefore sprouting has taken place or after sprouting.

The compounds of the invention are of particular value in the protectionof field, grassland, forage, plantation, glasshouse, orchard, grove andvineyard crops; or of vegetables and salads, of ornamental plantsflowers and shrubs and of plantation and forest trees.

The effective use doses of the compounds employed in the invention canvary within wide limits, particularly depending on the nature of thepest to be eliminated or degree of infestation. In general, thecompositions according to the invention usually contain about 0.05 toabout 95% (by weight) of one or more active ingredients according to theinvention, about 1 to about 95% of one or more solid or liquid carriersand, optionally, about 0.1 to about 50% of one or more other compatiblecomponents, such as surface-active agents or the like.

In the present account, the term “carrier” denotes an organic orinorganic ingredient, natural or synthetic, with which the activeingredient is combined to facilitate its application. This carrier istherefore generally inert and it must be acceptable (for example,agronomically acceptable, particularly to the treated plant).

The carrier may be a solid, for example, ground natural minerals, suchas attapulgite, bentonite, clays, chalk, diatomaceous earth, kaolins,montmorillonite, quartz, or talc, ground synthetic minerals, such asalumina, silica, or silicates, naturalsilicates, silica, resins, waxes,or solid fertilizers). As solid carriers for granules the following aresuitable: crushed natural rocks such as calcite, dolomite, marble,pumice, and sepiolite; synthetic granules of inorganic or organic meals;granules of organic material such as, coconut shells, corn cobs, cornhusks or sawdust; absorbent carbon black, kieselguhr, or powdered cork;water soluble polymers, resins, waxes; or solid fertilizers. Such solidcompositions may, if desired, contain one or more compatible wetting,dispersing, emulsifying or colouring agents which, when solid, may alsoserve as a diluent.

The carrier may also be liquid, for example: water; alcohols,particularly butanol or glycol, as well as their ethers or esters,particularly methyl glycol acetate; ketones, particularly acetone,cyclohexanone, methylethyl ketone, methylisobutylketone, or isophorone;petroleum fractions such as aliphatic or aromatic hydrocarbons,particularly xylenes; mineral or vegetable oils; chlorinatedhydrocarbons, particularly trichloroethane, methylene chloride orchlorobenzenes; water-soluble or strongly polar solvents such asdimethylformamide, dimethyl sulphoxide, or N-methylpyrrolidone; or amixture thereof.

The surface-active agent may be an emulsifying agent, dispersing agentor wetting agent of the ionic or non-ionic type or a mixture of suchagents. The presence of at least one surface-active agent is generallyessential when the active ingredient and/or the inert carrier are not oronly slightly water soluble and the carrier agent of the composition forapplication is water.

Compositions of the invention may further contain other additives suchas adhesives or colorants. Adhesives such as natural or syntheticphospholipids or carboxymethylcellulose or natural or synthetic polymersin the form of powders, granules or lattices, can be used in theformulations. It is possible to use colorants such as inorganicpigments, for example: iron oxides, titanium oxides or Prussian Blue;organic dyestuffs, such as alizarin dyestuffs, azo dyestuffs or metalphthalocyanine dyestuffs; or It is also possible to use trace nutrientssuch as salts of boron, cobalt, iron, manganese, copper, cobalt,molybdenum or zinc.

For their agricultural application, the compounds of the formula (I), orpesticidally acceptable salts thereof, are therefore generally in theform of compositions, which are in various solid or liquid forms.

Solid forms of compositions which can be used are dusting powders (witha content of the compound of formula (I), or a pesticidally acceptablesalt thereof, ranging up to 80%), wettable powders or granules(including water dispersible granules), particularly those obtained byextrusion, compacting, impregnation of a granular carrier, orgranulation starting from a powder (the content of the compound offormula (I), or a pesticidally acceptable salt thereof, in thesewettable powders or granules being between about 0.5 and about 80%).Solid homogenous or heterogenous compositions containing one or morecompounds of formula (I), or pesticidally acceptable salts thereof, forexample granules, pellets, briquettes or capsules, may be used to treatstanding or running water over a period of time. A similar effect may beachieved using trickle or intermittent feeds of water dispersibleconcentrates as described herein.

Liquid compositions, for example, include aqueous or non-aqueoussolutions or suspensions (such as emulsifiable concentrates, emulsions,flowables, dispersions, or solutions) or aerosols. Liquid compositionsalso include, in particular, emulsifiable concentrates, dispersions,emulsions, flowables, aerosols, wettable powders (or powder forspraying), dry flowables or pastes as forms of compositions which areliquid or intended to form liquid compositions when applied, for exampleas aqueous sprays (including low and ultra-low volume) or as fogs oraerosols.

Liquid compositions, for example, in the form of emulsifiable or solubleconcentrates most frequently comprise about 5 to about 80% by weight ofthe active ingredient, while the emulsions or solutions which are readyfor application contain, in their case, about 0.0 l to about 20% of theactive ingredient. Besides the solvent, the emulsifiable or solubleconcentrates may contain, when required, about 2 to about 50% ofsuitable additives, such as stabilizers, surface-active agents,penetrating agents, corrosion inhibitors, colorants or adhesives.Emulsions of any required concentration, which are particularly suitablefor application, for example, to plants, may be obtained from theseconcentrates by dilution with water. These compositions are includedwithin the scope of the compositions which may be employed in thepresent invention. The emulsions may be in the form of water-in-oil oroil-in-water type and they may have a thick consistency.

The liquid compositions of this invention may, in addition to normalagricultural use applications be used for example to treat substrates orsites infested or liable to infestation by arthropods (or other pestscontrolled by compounds of this invention) including premises, outdooror indoor storage or processing areas, containers or equipment orstanding or running water.

All these aqueous dispersions or emulsions or spraying mixtures can beapplied, for example, to crops by any suitable means, chiefly byspraying, at rates which are generally of the order of about 100 toabout 1,200 liters of spraying mixture per hectare, but may be higher orlower (eg. low or ultra-low volume) depending upon the need orapplication technique. The compounds or compositions according to theinvention are conveniently applied to vegetation and in particular toroots or leaves having pests to be eliminated. Another method ofapplication of the compounds or compositions according to the inventionis by chemigation, that is to say, the addition of a formulationcontaining the active ingredient to irrigation water. This irrigationmay be sprinkler irrigation for foliar pesticides or it can be groundirrigation or underground irrigation for soil or for systemicpesticides.

The concentrated suspensions, which can be applied by spraying, areprepared so as to produce a stable fluid product which does not settle(fine grinding) and usually contain from about 10 to about 75% by weightof active ingredient, from about 0.5 to about 30% of surface-activeagents, from about 0.1 to about 10% of thixotropic agents, from about 0to about 30% of suitable additives, such as anti-foaming agents,corrosion inhibitors, stabilizers, penetrating agents, adhesives and, asthe carrier, water or an organic liquid in which the active ingredientis poorly soluble or insoluble Some organic solids or inorganic saltsmay be dissolved in the carrier to help prevent settling or asantifreezes for water.

The wettable powers (or powder for spraying) are usually prepared sothat they contain from about 10 to about 80% by weight of activeingredient, from about 20 to about 90% of a solid carrier, from about 0to about 5% of a wetting agent, from about 3 to about 10% of adispersing agent and, when necessary, from about 0 to about 80% of oneor more stabilizers and/or other additives, such as penetrating agents,adhesives, anti-caking agents, colorants, or the like. To obtain thesewettable powders, the active ingredient(s) is(are) thoroughly mixed in asuitable blender with additional substances which may be impregnated onthe porous filler and is(are) ground using a mill or other suitablegrinder. This produces wettable powders, the wettability and thesuspendability of which are advantageous. They may be suspended in waterto give any desired concentration and this suspension can be employedvery advantageously in particular for application to plant foliage.

The “water dispersible granules (WG)” (granules which are readilydispersible in water) have compositions which are substantially close tothat of the wettable powders. They may be prepared by granulation offormulations described for the wettable powders, either by a wet route(contacting finely divided active ingredient with the inert filler and alittle water, e.g. 1 to 20% by weight, or with an aqueous solution of adispersing agent or binder, followed by drying and screening), or by adry route (compacting followed by grinding and screening).

The rates and concentrations of the formulated compositions may varyaccording to the method of application or the nature of the compositionsor use thereof. Generally speaking, the compositions for application tocontrol arthropod, plant nematode, helminth or protozoan pests usuallycontain from about 0.00001% to about 95%, more particularly from about0.0005% to about 50% by weight of one or more compounds of formula (I),or pesticidally acceptable salts thereof, or of total active ingredients(that is to say the compound of formula (I), or a pesticidallyacceptable salt thereof, together with: other substances toxic toarthropods or plant nematodes, anthelmintics, anticoccidials,synergists, trace elements or stabilizers). The actual compositionsemployed and their rate of application will be selected to achieve thedesired effect(s) by the farmer, livestock producer, medical orveterinary practitioner, pest control operator or other person skilledin the art.

They are also valuable in the protection of timber (standing, felled,converted, stored or structural) from attack by sawflies or beetles ortermites. They have applications in the protection of stored productssuch as grains, fruits, nuts, spices and tobacco, whether whole, milledor compounded into products, from moth, beetle and mite attack. Alsoprotected are stored animal products such as skins, hair, wool andfeathers in natural or converted form (e.g. as carpets or textiles) frommoth and beetle attack; also stored meat and fish from beetle, mite andfly attack. Solid or liquid compositions for application topically totimber, stored products or household goods usually contain from about0.00005% to about 90%, more particularly from about 0.001% to about 10%,by weight of one or more compounds of formula (I) or pesticidallyacceptable salts thereof.

The compounds of the invention (and their pharmaceutically, veterinarilyand agriculturally acceptable salts) may be used, for example, in thefollowing applications and on the following pests:

In the field of veterinary medicine or livestock husbandry or in themaintenance of public health against arthropods which are parasiticinternally or externally upon vertebrates, particularly warm-bloodedvertebrates, including man and domestic animals such as dogs, cats,cattle, sheep, goats, equines, swine, poultry and fish. Also, in thefield of control of plant pests, soil inhabiting pests and otherenvironmental pests. Illustrative of specific parasites which may becontrolled by the compounds of this invention include arthropods suchas:

Actinedida/Acaridida: chicken mite (Mesostigmata spp e.g. Dermanyssusgallinae); itch/scab mites (Sarcoptes spp e.g. Sarcoptes scabiei) mangemites (Psoroptes spp e.g. Psoroptes ovis, Chorioptes spp e.g. Chorioptesbovis); chiggers (Trombicula spp e.g. Trombicula aifteddugesi);Damalinia spp; Demodex spp; Acarapis spp; Cheyletiella spp;Ornithocheyletia spp; Myobia spp; Listrophorus spp; Acarus spp;Tyrophagus spp; Caloglyphus spp; Hypodectes spp; Pterolichus spp;Otodectes spp; Notoedres spp; Cytodites spp; Knemidocoptes spp;Laminiosioptes spp.

Siphonapterida: Ctenocephalides spp e.g. Ctenocephalides canis,Ctenocephalides fells; Xenopsylla spp e.g. Xenopsylla cheopis; Pulex sppe.g. Pulex irritans; Ceratophyllus spp.

Ticks: Argas spp e.g. Argas persicus; Ornithodorus spp e.g. Ornithodorusmoubata; Otobius spp e.g. Otobius megnini; Ixodes spp e.g. Ixodesricinus, Ixodes rubicundus; Amblyomma spp e.g. Amblyomma americanum,Amblyomma variegatum; Boophilus spp e.g. Boophilus annulatus, Boophilusdecoloratus, Boophilus microplus; Dermacentor spp e.g. Dermacentorsilvarum; Haemophysalis spp; Hyalomma spp e.g. Hyalomma truncatum;Rhipicephalus spp e.g. Rhipicephalus sanguineus, Rhipicephalusappendiculatus, Rhipicephalus evertsi; Dermanyssus spp; Railletia spp;Pneumonyssus spp; Stemostoma spp; Varroa spp; and other ticks e.g.Brevipalpus phoenicis, Bryobia praetiosa, Eotetranychus carpini,Eriophyes sheldoni, Paratetranychus pilosus, Phyllocoptruta oleivora,Polyphagotarsonemus latus, Tetranychus cinnabarinus, Tetranychuskanzawai, Tetranychus pacificus, Tetranychus telarius.

Adult flies (Diptera): Horn fly (Haematobia irritans); Horse fly(Tabanus spp e.g. Tabanus bovines); Stable fly (Stomoxys calcitrans);Black fly (Simulium spp); Deer fly (Chrysops spp); Louse fly (Melophagusovinus); Tsetse fly (Glossina spp e.g. Glossina morsitans); Mosquitoes(Culex spp e.g. Culex pipiens; Anopheles spp e.g. Anophelesmaculipennis; Aedes spp e.g. Aedes egypti, Aedes vexans); Eusimuliumspp; Phlebotonius spp; Lutzomyia spp; Culicoides spp; Hybomitra spp;Atylotus spp; Haematopota spp; Philipomyia spp; Braula spp; Hydrotaeaspp; Morellia spp; Fannia spp e.g. Fannia canucularis; Calliphora spp;Wohlfahrtia spp; Sarcophaga spp; Hippobosca spp; Lipoptena spp;Melophagus spp; and other Diptera such as Anastrepha ludens; Ceratitiscapitata; Chrysomya bezziana; Chrysomya hominivorax; Chrysomyamacellaria; Contarinia sorghicola; Cordylopia anthropophaga; Dacuscucurbitae; Dasineura brassicae; Gasterophilus intestinalis;Haplodiplosis equestris; Hylemyia platura; Hypoderma lineata; Liriomyzasativae; Liriomyza trifolii; Lycoria pectoralis; Mayettiola destructor;Musca domestica; Muscina stabulans; Oestrus ovis; Oscinella frit;Pegomya hysocyami; Phorbia brassicae; Phorbia coarctata; Rhagoletiacerasi; Rhagoletis pomonella; Tipula oleraceam; Tipula paludosa; andalso Blow flies; Soldierflies; Midges and Punkies.

Parasitic fly maggots: Bot fly (Oestrus ovis, Cuterebra spp); Blow fly(Phaenicia spp, Lucilia sericata, Lucilia cuprina); Screwworm(Cochliomyia hominivorax); Cattle grub (Hypoderma spp); Dermatobiahominis.

Anoplurida: sucking lice (Menopon spp; Bovicola spp); biting lice(Haematopinus spp; Linognathus spp; Solenoptes spp; Phtirus spp).

True bugs: common bed bug (Cimicidae e.g. Cimex lectularius); kissingbugs (Triatoma spp e.g. Rhodnius prolixus).

Brachycera: Black flies; Biting midges; Sand flies; Sciarids.

Orthoptera: Periplaneta spp; Blatella spp e.g. Blatella germanica;Gryllotalpa spp e.g. Gryllotalpa gryllotalpa; Acheta domestica; Blattaorientalis Forficula auricularia; Leucophaea maderae; Melanoplusbivittatus; Melanoplus femur-rubrum; Melanoplus mexicanus; Melanoplussanguinipes; Melanoplus spretus; Momadacris septemfasciata; Schistocercaperegrina; Stauronotus maroccanus; Tachycines asynamorus.

Dictyoptera: Periplaneta fuliginosa; Periplaneta japonica; PeriplanetaAmericana.

Hymenoptera: Carpenter ants; Bees; Hornets; Wasps.

Lepidoptera: Adoxophyes orana fasciata; Agrotis ypsilon; Agrotissegetum; Alabama argillacea Hubner; Anticarsia gemmatalis; Archipsargyrospila Walker; Archips rosana; Argyresthia conjugella; Autographagamma; Autographa nigrisigna Barathra brassicae; Bupalus piniarius;Cacoecia murinana; Caloptilia theivora; Capua reticulana; Carposinaniponensis; Chematobia brumata; Chilo polychrysus; Chilo suppressalisWalker, Choristoneura fumiferana; Choristoneura occidentalis; Cirphisunipuncta; Cnaphalocrosis medinalis Guenee; Cydia pomonella; Dendrolimuspini; Diaphania nitidalis; Diatraea grandiosella; Earias insulanaBoisduval; Earias vittella Fabricius; Elasmopalpus lignosellus;Eupoecilia ambiguella; Evetria bouliana; Feltia subterrana; Galleriamellonella; Grapholitha funebrana; Grapholitha molesta; Helicoverpaarmigera; Helicoverpa assulta; Helicoverpa zea; Heliothis virescens;Hellula undalis; Hibernia defoliaria; Hyphantria cunea; Hyponomeutamalinellus; Keiferia lycopersicella; Lambdina fiscellaria; Laphygmaexigua; Leucoptera coffeella; Leucoptera scitella; Lithocolletisblancardella; Lobesia botrana; Loxostege sticticalis; Lymantria monacha;Lyonetia clerkella; Malacosoma neustria; Mamestra brassicae; Narangaaenescens; Notarcha derogata; Orgyia pseudotsugata; Ostrinia nubilalis;Ostrinia fumacalis; Parnara guttata; Panolis flammea; Pectinophoragossypiella; Peridroma saucia; Phalera bucephala; Phyllocnistiscitrella; Pieris brassicae; Pieris rapae; Plutella xylostella;Pseudaletia separate; Phthorimaea operculella; Phyllonorycterringoneells; Plathypena scabra; Pseudoplusia includens; Rhyacioniafrustrana; Scrobipalpula absoluta; Sitotroga cerealella; Sparganothispilleriana; Spodoptera exigua; Spodoptera frugiperda; Spodopteralittoralis; Spodoptera litura; Thaumatopoea pityocampa; Tortrixviridans; Trichoplusia ni Hubner, Tryporyza incertulas; Tuta absoluta;Zeiraphera Canadensis; Lyonetid moths; Tussock moths; Casemaking clothesmoth; Webbing clothes moth.

Coleoptera: Agrilus sinuatus; Agriotes lineatus; Agriotes obscurus;Amphimellus solstitialis; Anisandrus dispar; Anobium punctatum;Anoplophora malasiaca; Anthonomus grandis; Anthonomus pomorum; Anthrenusverbasci; Apate monachus; Atomaria linearis; Aulacophora femoralis;Blastophagus piniperda; Blitophaga undata; Bostrychos capucins; Bruchusrufimanus; Bruchus pisorum; Bruchis lentis; Byctiscus betulae;Callosobruchus chinensis; Cassida nebulosa; Cerotoma trifurcata;Ceuthorrhynchus assimilis; Ceuthorrhynchus napi; Chaetocnema tibialis;Chlorophorus pilosis; Conoderus vespertinus; Crioceris asparagi;Diabrotica longicomis; Dendrobium pertinex; Diabrotica 12-punctata;Diabrotica virgifera; Dinoderus minutes; Echinocnemus squameus;Elilachna vigintioctopunctata; Ernobius mollis; Epilachna varivestis;Epitrix hirtipennis; Eutinobothrus brasiliensis; Heterobostrychusbrunneus; Hylobius abietis; Hylotrupes bajulus; Hypera brunneipennis;Hypera postica; Ips typographus; Lasioderma serricome; Lema bilineata;Lema melanopus; Limonius californicus; Lissorhoptus oryzophilus; Lyctusbrunneus; Lyctus linearis; Lyctus pubescens; Melanotus communis;Meligethes aeneus; Melolontha hippocastani; Melolontha melolontha;Minthes rugicollis; Oulema oryzae; Ortiorrhynchus sulcatus;Otiorrhynchus ovatus; Paederus fuscipes; Phaedon cochleariae;Phyllotreta chrysocephala; Phyllophaga spp; Phyllopertha horticola;Phyllotreta nemorum; Phyllotreta striotata; Popillia japonica; Priobiumcarpini; Ptilinus pecticornis; Sitona lineatus; Sitophilus granaria;Sphenophorus venatus; Tomicus piniperda; Tribolium castaneum; Trogoxylonaequale; Xestobium rufovillosum; Aupreous chafer; Western corn rootworm;Rice water weevil; Adzuki bean beetle; Yellow mealworm; Red flourbeetle; Striped flea beetle; Cucurbit leaf beetle; Deathwatch beetle;Drugetose beetle; Mexican bean beetle; Flea beetle; Japanese beetle;Boll weevil; Rice water weevil; Granary weevil; Rice weevil; Wireworms(Agriotes spp; Athous spp; Limonius spp); Xyleborus spp; Tryptodendronspp; Sinoxylon spp;

Homoptera: Acyrthosiphon onobrychis; Adelges laricis; Aleurodesbrassicae; Aphidula nasturtii; Aphis fabae; Aphis gossypii; Aphis pomi;Aphis sambuci; Aspiodotus hederae; Bemisia tabaci; Bemisia argentifolii;Brachycaudus cardui; Brevicoryne brassicae; Cerosipha gossypii;Cryptomyzus ribis; Diuraphis noxia; Dreyfusia nordmannianae; Dreyfusiapiceae; Dysaphis radicola; Dysaulacorthum pseudosolani; Empoasca fabae;Eriosoma lanigerum; Euscelis bilobatus; Hyalopterus arundinis;Laodelphax stiatellus; Lecanium comi; Macrosiphum avenae; Macrosiphumeuphorbiae; Macrosiphon rosae; Megoura viciae; Metolophium dirhodum;Myzodes persicae; Myzus cerasi; Myzus persicae; Nilaparvata lugens;Pemphigus bursarius; Perkinsiella saccharicida; Phorodon humuli; Psyllamall; Psylla piri; Rhopalomyzus ascalonicus; Rhopalosiphum maidis;Rhopalosiphum padi; Saissetia oleae; Sappaphis mala; Sappaphis mali;Schizaphis graminum; Schizoneura lanuginose; Sitobion avenae;Trialeurodes vaporariorum; Vites vitifolii.

Hemiptera: Aulacorthum solani; Aphis glycines; Eysarcoris parvus;Eurydema rugosum; Icerva purchasi; Laodelphax striatellus; Lipaphisetysimi; Nephotettix cincticeps; Planococcus citri; Pseudococcuscomstocki; Riptortus clavatus; Scotinophora lurida; Sogatella furcifera;Stephanitis nashi; Unaspis vanonensis; Small brown planthopper; Brownrice planthopper; Whitebacked rice planthopper; Stink bugs; Whiteflies;Lace bugs, Jumping plantlice.

And species of the orders: Hymenoptera; Isoptera; Isopoda; Diplopoda;Chilopoda; Symphyla; Thysanura; Dermaptera; and Heteroptera;

In the field of veterinary medicine or livestock husbandry or in themaintenance of public health for controlling helminths, nematodes andprotozoa such as:

Trematoda: Fasciola; Fascioloides; Paramphistomum; Dicrocoelium;Eurytrema; Ophisthorchis; Fasciolopsis; Echinostoma; Paragonimus.

Nematodes: Haemonchus; Ostertagia; Cooperia; Oesphagastomum;Nematodirus; Dictyocaulus; Trichuris; Dirofilaria; Ancyclostoma;Ascaris; Trichostrongylus.

Protozoa: Eimeria spp; Leishmania spp; Plasmodium spp; Babesis spp;Trichomonadidae spp; Toxoplasma spp and Theileria spp.

In the protection of stored products, for example cereals, includinggrain or flour, groundnuts, animal feedstuffs, timber or householdgoods, e.g. carpets and textiles, compounds of the invention are usefulagainst attack by arthropods such as:

Flour moths (Ephestia spp); Carpet beetles (Anthrenus spp); Flourbeetles (Tribolium spp); Grain weevils (Sitophilus spp); Mites (Acarusspp)

In the protection against soil inhabiting insects such as:

Western corn rootworm, other Diabrotica spp, European chafer and othercoleopteran grubs, and wireworms; adults and larvae of the ordersHemiptera and Homoptera including tarnished plant bug and other plantbugs (Miridae), aster leafhopper and other leaf hoppers (Cicadellidae),rice plant hopper, brown planthopper, and other planthoppers(Fulgoroidae), paylids, whiteflies (Aleurodidae), aphids (Aphidae),scales (Coccidae and Diaspididae), lace bugs (Tingidae), stink bugs(Pentamodidae), cinch bugs and other seed bugs (Lygaeidae), cicadas(Cicadidae), spittlebugs (Cercopids), squash bugs (Coreidae), red bugsand cotton stainers (Pyrrhocoridae); adults and larvae of the orderacari including European red mite, two spotted mite, rust mites,McDaniel mite and other foliar feeding mites; adults and immatures ofthe order Orthoptera including grasshoppers; adults and immatures of theorder Diptera including leafminers, midges, fruit flies (Tephritidae),and soil maggots; adults and immatures of the order Thysanopteraincluding onion thrips and other foliar feeding thrips.

For the avoidance of doubt, references herein to “treatment” includereferences to curative, palliative and prophylactic treatment,references to “control” (of parasites and/or pests etc.) include kill,repel, expel, incapacitate, deter, eliminate, alleviate, minimise,eradicate.

The compounds of the invention are of particular value in the control ofarthropods which are injurious to, or spread or act as vectors ofdiseases in, man and domestic animals, for example those hereinbeforementioned, and more especially in the control of ticks, mites, lice,fleas, midges and biting, nuisance and myiasis flies. They areparticularly useful in controlling arthropods which are present insidedomestic host animals or which feed in or on the skin or suck the bloodof the animal, for which purpose they may be administered orally,parenterally, percutaneously or topically.

Regarding the use of the compounds of the invention in mammals, there isprovided: a pharmaceutical or veterinary parasiticidal compositioncomprising a compound of formula (I), or a pharmaceutically orveterinarily acceptable salt thereof, or a pharmaceutically orveterinarily acceptable solvate of either entity, together with apharmaceutically or veterinarily acceptable diluent or carrier, whichmay be adapted for oral, parenteral or topical administration;

a compound of formula (I), or a pharmaceutically or veterinarilyacceptable salt thereof, or a pharmaceutically or veterinarilyacceptable solvate of either entity, or a pharmaceutical or veterinarycomposition containing any of the foregoing, for use as a medicament;the use of a compound of formula (I), or a pharmaceutically orveterinarily acceptable salt thereof, or a pharmaceutically orveterinarily acceptable solvate of either entity, or a pharmaceutical orveterinary composition containing any of the foregoing, for themanufacture of a medicament for the treatment of a parasiticinfestation; anda method of treating a parasitic infestation in a mammal which comprisestreating said mammal with an effective amount of a compound of formula(I), or a pharmaceutically or veterinarily acceptable salt thereof, or apharmaceutically or veterinarily acceptable solvate of either entity, ora pharmaceutical or veterinary composition containing any of theforegoing.

According to another aspect of the present invention, there is provideda method for the control of arthropod, plant nematode or helminth pestsat a locus which comprises the treatment of the locus (e.g. byapplication or administration) with an effective amount of a compound ofgeneral formula I, or a pesticidally acceptable salt thereof.

The present invention also relates to a method of cleaning animals ingood health comprising the application to the animal of compound offormula (I) or a veterinarily acceptable salt. The purpose of suchcleaning is to reduce or eliminate the infestation of humans withparasites carried by the animal and to improve the environment whichhumans inhabit.

The flea membrane feed test is used to measure the biological activitiesof the compounds claimed. The assay involves in vitro testing againstCtenocephalides felis conducted according to the following generalprocedure.

Fleas are cultured in vitro using dog blood. 25-30 adult Ctenocephalidesfelis (cat flea) were collected and placed in a test chamber (50 mlpolystyrene tube with fine nylon mesh sealing the end). Citrated dogblood was prepared by adding aqueous sodium citrate solution (10 ml, 20%w/v, 20 g sodium citrate in 100 ml water) to dog blood (250 ml). Testcompounds were dissolved in dimethylsulfoxide to give a working stocksolution of 4 mg/ml. The stock solution (12.5 μl) was added to citrateddog blood (5 ml) to give an initial test concentration of 10 μg/ml. Fortesting at 30 μg/ml, working stock solutions of 12 mg/ml were prepared.

Citrated dog blood containing the test compound (5 ml, 10 μg/ml) wasplaced into a plastic Petri dish lid, which was kept at 37° C. on aheated pad. Parafilm was stretched over the open top to form a tightmembrane for the fleas to feed through. The test chamber containing thefleas was placed carefully onto the parafilm membrane and the fleascommenced feeding.

The fleas were allowed to feed for 2 hours and the test chambers werethen removed and stored overnight at room temperature.

The fleas were observed and the percentage of fleas killed recorded.Compounds were initially tested at 10 μg/ml, wherefrom relevant doseresponses (100, 30, 10, 3, 1, 0.3, 0.1 μg/ml) were conducted andrepeated n=5. Data was plotted to generate ED80, ED90 & ED95 values.

The compounds of the present invention have significantly betteractivity than the prior art compounds. All the examples of the presentinvention have flea ED80 values of less than 100 μg/ml. Results for someof the compounds are presented below.

Example Flea feed ED80 results 5 1 84 3 27 0.1

Instruments used to acquire characterising data

Nuclear magnetic resonance spectral data were obtained using Varian(nova 300, Varian (nova 400, Varian Mercury 400, Varian Unityplus 400,Bruker AC 300 MHz, Bruker AM 250 MHz or Varian T60 MHz spectrometers,the observed chemical shifts being consistent with the proposedstructures. Mass spectral data were obtained on a Waters Micromass ZQ,or a Hewlett Packard GCMS System Model 5971 spectrometer. The calculatedand observed ions quoted refer to the isotopic composition of lowestmass. HPLC means high performance liquid chromatography. Roomtemperature means 20 to 25° C.

Compounds of the present invention are exemplified below.

EXAMPLE 1N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2-difluoroethyl)methanesulfonamide

To a mixture ofN-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}methanesulfonamide(200 mg, 0.42 mmol) and 2,2-difluoroethyl trifluoromethanesulphonate(600 mg, 2.80 mmol) in acetonitrile (12 ml) was added potassiumcarbonate (116 mg, 0.84 mmol). The reaction mixture was then stirred at40° C. for 1 h. To the reaction mixture was added water (10 ml) and themixture was extracted with diethyl ether (2×8 ml). The combined extractswere dried (MgSO₄) and concentrated in vacuo. The residue was dissolvedin acetonitrile (1.5 ml) and the solution was purified by automatedpreparative liquid chromatography (Gilson system, 150 mm×30 mmPhenomonex LUNA II 10 μm C18 column) using an acetonitrile:watergradient [50:50 to 98:2]. The appropriate fractions were concentrated invacuo to give the titled compound (145 mg).

Experimental MH⁺ 535.9; expected 536.0.

¹H-NMR (DMSO): 3.05-3.09 (3H), 3.53-3.77 (1H), 3.86-4.09 (1H), 5.99-6.27(1H), 6.53-6.61 (2H), 8.41-8.45 (2H)

EXAMPLE 2N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-1,1,1-trifluoro-N-methylmethanesulfonamide

To Preparation 14 in methanol (5 ml) was added hydrochloric acid (4N, 3ml) and the reaction mixture was heated at 80° C. overnight. Thereaction mixture was concentrated in vacuo and the residue waspartitioned between ethyl acetate (20 ml) and water (20 ml). The organiclayer was separated, washed with water (2×20 ml), dried (Na₂SO₄) andconcentrated in vacuo. The crude product was dissolved in a mixture ofacetonitrile, dimethyl sulphoxide and water (4:5:1, 2 ml) and purifiedby automated preparative liquid chromatography (Gilson system, 150 mm×30mm Phenomonex LUNA C18(2) 10 μm column) using an acetonitrile:watergradient [60:40 to 95:5]. The appropriate fractions were concentrated invacuo to give the titled compound (60 mg).

Experimental MH⁺ 539.9; expected 539.9

¹H-NMR (CDCl3): 3.53-3.55 (3H), 4.08-4.12 (2H), 7.89-7.92 (2H)

Similarly prepared were:

From Ex R1a R2 R4 R3 prep. 3 CF₃ CN H 3,4-difluorophenyl 1 4 ′ ′cyclopropylmethyl Me 6 5 ′ ′ cyanomethyl Me 7 6 ′ ′ pyridin-2-ylmethylMe 8 7 ′ ′ benzyl Me 9 8 ′ ′ 2-(N,N- Me 13 dimethylamino)ethyl 9 ′ ′ Hmethylsulfonylmethyl 2 10 ′ ′ 2-hydroxyethyl Me 10 11 ′ ′methylthiomethyl Me 11 12 ′ ′ cyclopropylsulfonyl Me 17 13 ′ ′N,N-dimethylsulfonyl Me 18 14 ′ ′ methylsulfonyl Me 12 15 ′ ′ H Me 15 16′ ′ H benzyl 4 17 ′ ′ H 2-phenylethenyl 5 18 SF₅ CF₃ methylsulfonyl Me20 19 CF₃ CN

50

EXAMPLE 3

Experimental MH⁺ 512.0; expected 512.0

¹H-NMR (CDCl3): 3.46-3.46 (2H), 6.28-6.31 (1H), 7.32-7.38 (1H),7.56-7.61 (2H), 7.77-7.79 (2H)

EXAMPLE 4

Experimental MH⁺ 468.2; expected 468.0

¹H-NMR (CDCl3): 0.17-0.23 (2H), 0.50-0.56 (2H), 0.97-1.05 (1H),3.06-3.07 (3H), 3.50-3.55 (2H), 4.15-4.19 (2H), 7.77-7.78 (2H)

EXAMPLE 5

Experimental MH⁺ 453.2; expected 453.0

¹H-NMR (CDCl3): 3.08-3.12 (3H), 3.30-3.39 (2H), 4.49-4.52 (2H),7.69-7.72 (2H)

EXAMPLE 6

Experimental MH⁺ 505.3; expected 505.0

¹H-NMR (CDCl3): 3.06-3.08 (3H), 4.91-4.98 (2H), 7.23-7.28 (2H),7.32-7.36 (1H), 7.71-7.73 (2H), 8.51-8.54 (1H)

EXAMPLE 7

Experimental MH⁺ 504.3; expected 504.0

¹H-NMR (CDCl3): 3.15-3.16 (3H), 3.66-3.71 (2H), 7.24-7.28 (3H),7.29-7.33 (2H), 7.67-7.69 (2H)

EXAMPLE 8

Experimental MH⁺ 485.0; expected 485.1

¹H-NMR (CDCl3): 2.19-2.38 (6H), 2.41-2.57 (2H), 3.10-3.15 (3H),3.70-3.94 (2H), 4.97-5.23 (2H), 7.75-7.78 (2H)

EXAMPLE 9

Experimental MH⁺ 491.9; expected 492.0

¹H-NMR (DMSO): 3.19-3.22 (3H), 4.98-5.03 (2H), 6.19-6.28 (2H), 8.19-8.25(2H), 9.83-9.87 (1H)

EXAMPLE 10

Experimental MH⁺ 458.0; expected 458.0

¹H-NMR (CD3OD): 3.07-3.08 (3H), 3.61-3.75 (4H), 7.98-8.01 (2H)

EXAMPLE 11

¹H-NMR (CDCl3): 2.23-2.25 (3H), 3.10-3.12 (3H), 4.21-4.25 (2H),4.76-4.80 (2H), 7.77-7.78 (2H)

EXAMPLE 12

Experimental MH⁺ 517.9; expected 518.0

¹H-NMR (CD3OD): 1.18-1.26 (4H), 3.06-3.10 (1H), 3.45-3.46 (3H),7.55-7.59 (2H)

EXAMPLE 13

Experimental MH⁺ 520.9; expected 521.0

¹H-NMR (CDCl3): 2.98-3.02 (6H), 3.44-3.47 (3H), 4.25-4.33 (2H),7.76-7.80 (2H)

EXAMPLE 14

Experimental MH⁺ 491.9; expected 492.0

¹H-NMR (CDCl3): 3.44-3.54 (6H), 4.11-4.23 (2H), 7.75-7.85 (2H)

EXAMPLE 15

Experimental MH⁺ 414.0; expected 414.0. ¹H-NMR (CD3OD): 3.02-3.07 (3H),7.97-8.02 (2H)

EXAMPLE 16

Experimental MH⁺ 490.0; expected 490.0

¹H-NMR (CD3OD): 4.41-4.44 (2H), 7.30-7.37 (3H), 7.41-7.46 (2H),7.95-8.01 (2H)

EXAMPLE 17

Experimental MH⁺ 502.0; expected 502.0

¹H-NMR (CD3OD): 6.97-7.03 (1H), 7.25-7.31 (1H), 7.35-7.40 (3H),7.52-7.56 (2H), 7.90-7.95 (2H)

EXAMPLE 18

Experimental MH⁺ 592.9; expected 592.9

¹H-NMR (CDCl3): 3.38-3.42 (6H), 4.06-4.12 (2H), 7.89-7.92 (2H)

EXAMPLE 19

Experimental MW 440.0; expected 440.0

¹H-NMR (CDCl3): 2.54-2.67 (2H), 3.33-3.44 (2H), 3.79-3.89 (2H),4.20-4.36 (2H), 7.73-7.81 (2H)

EXAMPLE 20N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-1,1,1-trifluoro-N-methylmethanesulfonamide

To a solution ofN-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)-1,1,1-trifluoro-N-methylmethanesulfonamide(240 mg, 0.45 mmol) in methanol (7 ml) was added hydrochloric acid (4N,4 ml) and the reaction mixture was heated at reflux for 4 h. Thereaction mixture was concentrated under nitrogen and the residuepartitioned between ethyl acetate and water. The two layers wereseparated and the aqueous layer was extracted with ethyl acetate (×2).The combined organic phases were dried (MgSO₄) and concentrated undernitrogen. The crude product was dissolved in acetonitrile (4 ml) andpurified by automated preparative liquid chromatography (Gilson system,150 mm×21.2 mm Phenomonex LUNA 100A C18 column) using anacetonitrile:water gradient [50:50 to 98:2]. The appropriate fractionswere concentrated in vacuo to give the titled compound (105 mg).

Experimental MH⁺ 482.0; expected 482.0

¹H-NMR (CDCl3): 3.50-3.52 (3H), 4.00-4.10 (2H), 7.71-7.76 (2H)

EXAMPLE 21N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(cyclopropylmethyl)-1,1,1-trifluoromethanesulfonamide

To a solution ofN-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)-1,1,1-trifluoromethanesulfonamide(250 mg, 0.48 mmol) in acetone (6 ml) was added potassium carbonate (100mg, 0.72 mmol), a catalytic amount of sodium iodide and(bromomethyl)cyclopropane (69.5 μl, 0.72 mmol). The reaction mixture wasthen stirred at 60° C. overnight. The reaction mixture was concentratedunder a stream of nitrogen and the residue was partitioned betweendichloromethane (20 ml) and water (20 ml). The two layers were separatedand the organic phase was washed with water, dried (Na₂SO₄) andconcentrated in vacuo to give the protected compound. To a solution ofthe protected compound in methanol (5 ml) was added hydrochloric acid(4M, 3 ml) and the reaction mixture was heated at reflux. The reactionmixture was concentrated in vacuo and the residue was extracted withethyl acetate (20 ml). The organic phase was washed with water (2×20ml), dried (Na₂SO₄) and concentrated in vacuo. The crude product wasdissolved in a mixture of acetonitrile (1 ml), dimethyl sulphoxide (2.4ml) and water (0.6 ml) and purified by automated preparative liquidchromatography (Gilson system, 150 mm×30 mm Phenomonex LUNA C18(2) 10 μmcolumn) using an acetonitrile:water gradient [60:40 to 95:5]. Theappropriate fractions were concentrated in vacuo to give the titledcompound (120 mg).

Experimental MH⁺ 522.3; expected 522.0

¹H-NMR (CDCl3): 0.19-0.29 (2H), 0.54-0.64 (2H), 0.99-1.10 (1H),3.53-3.78 (2H), 4.01-4.13 (2H), 7.72-7.84 (2H)

EXAMPLE 22N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide

To a solution ofN-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)methanesulfonamide(250 mg, 0.53 mmol) in 1-methyl-2-pyrrolidinone (anhydrous, 5 ml) wasadded sodium hydride (60% in oil, 16.6 mg, 0.69 mmol) and2,2,2-trifluoroethyl trichloromethanesulphonate (195 mg, 0.69 mmol). Thereaction mixture was then stirred at room temperature for 3 h. To thereaction mixture was added dichloromethane (20 ml) and the resultingmixture was extracted with water (20 ml). The organic phase was washedwith water (2×20 ml) and brine (2×20 ml), dried (Na₂SO₄) andconcentrated in vacuo. To the residue was added methanol (5 ml) andhydrochloric acid (4M, 3 ml) and the mixture was heated at reflux for 60h. The reaction mixture was concentrated in vacuo and to the residue wasadded ethyl acetate (20 ml) and water (20 ml). The organic phase wasseparated, washed with water (2×20 ml) and brine (2×20 ml), dried(Na₂SO₄) and concentrated in vacuo. The crude product was dissolved inacetonitrile/dimethyl sulphoxide/water (1:4:1, 6 ml) and purified byautomated preparative liquid chromatography (Gilson system, 150 mm×30 mmPhenomonex LUNA C18(2) 10 μm column) using an acetonitrile:watergradient [52.5:47.5 to 95:5]. The appropriate fractions wereconcentrated in vacuo to give the titled compound (135 mg).

Experimental MH⁺ 496.2; expected 496.0

¹H-NMR (CDCl3): 3.10-3.14 (3H), 4.07-4.33 (4H), 7.74-7.80 (2H)

EXAMPLE 23N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-1,1,1-trifluoro-N-(methylsulfonyl)methanesulfonamide

To a solution ofN-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}methanesulfonamide(73 mg, 0.18 mmol) in dichloromethane (4 ml), at 0° C., was addeddropwise triethylamine (30 μl, 0.21 mmol), followed bytrifluoromethanesulphonic anhydride (30 μl, 0.18 mmol). The reactionmixture was allowed to warm to room temperature and stirred for 4 h. Tothe reaction mixture was added water and dichloromethane. The two layerswere separated and the aqueous layer was extracted with dichloromethane(×3). The combined organic phases were then dried (MgSO₄) andconcentrated in vacuo. The crude product was dissolved inacetonitrile/water (7:3, 5 ml) and purified by automated preparativeliquid chromatography (Gilson system, 150 mm×30 mm Phenomenex LUNAC18(2) 10 μm column) using an acetonitrile:water gradient [55:45 to95:5]. The appropriate fractions were concentrated in vacuo to give thetitled compound (50 mg).

Experimental MH⁺ 543.9; expected 543.9

¹H-NMR (CDCl3): 3.57-3.58 (3H), 4.12-4.20 (2H), 7.77-7.81 (2H)

EXAMPLE 24N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-[(methylsulfonyl)methyl]methanesulfonamide

To a solution ofN-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-[(methylthio)methyl]methanesulfonamide(108 mg, 0.23 mmol) in acetone (35 ml) was added sodium carbonate (318mg, 3.04 mmol), followed by Oxone® (924 mg, 1.52 mmol) in water (12 ml).The reaction mixture was then stirred at room temperature for 5 h. Tothe reaction mixture was added water and the solution was extracted withethyl acetate. The combined extracts were washed with brine, dried(MgSO₄) and concentrated in vacuo. The crude product was dissolved in amixture of acetonitrile (1 ml) and water (1 ml) and purified byautomated preparative liquid chromatography (Gilson system, 150 mm×30 mmPhenomenex LUNA C18(2) 10 μm column) using an acetonitrile:watergradient [45:55 to 95:5]. The appropriate fractions were concentrated invacuo to give the titled compound (55 mg).

Experimental MH⁺ 505.9; expected 506.0

¹H-NMR (CDCl3): 3.05-3.07 (3H), 3.15-3.18 (3H), 4.43-4.54 (2H),7.74-7.80 (2H)

EXAMPLE 25 N-{5-amH-pyrazol-4-yl}-N-cyclobutyl-1,1,1-trifluoromethanesulfonamide

To a solution of Preparation 12 (250 mg, 0.43 mmol) in tetrahydrofuran(15 ml) was added hydrochloric acid (4M, 15 ml). The reaction mixturewas then heated at reflux overnight. The reaction mixture wasconcentrated in vacuo and the residue was partitioned between water (50ml) and dichloromethane (75 ml). The organic layer was separated, dried(Na₂SO₄) and concentrated in vacuo. The crude product was dissolved inacetonitrile (6 ml) and the solution was passed through a 0.45μ filter.The solution was then purified by automated preparative liquidchromatography (Gilson system, 150 mm×30 mm Phenomonex LUNA II 10μ C18column) using an acetonitrile:water gradient [60:40 to 95:5]. Theappropriate fractions were concentrated in vacuo to give the titledcompound (113 mg).

Experimental MH⁺ 522.0; expected 522.0

¹H-NMR (Acetone): 0.23-0.31 (2H), 0.56-0.64 (2H), 1.12-1.20 (1H),3.56-3.78 (2H), 6.12-6.22 (2H), 8.02-8.13 (2H)

EXAMPLE 26N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide

To a solution of Preparation 23 (200 mg, 0.45 mmol) in anhydrousdichloromethane (5 ml), at 0° C., was added triethylamine (124 μl, 0.9mmol) and methanesulphonyl chloride (70 μl, 0.9 mol). The reactionmixture was then stirred under nitrogen for 30 min. To the reactionmixture was added dichloromethane (20 ml) and the resulting mixture wasextracted with water (20 ml). The organic phase was washed with water(2×20 ml) and brine (2×20 ml), dried (Na₂SO₄) and concentrated in vacuo.To the residue was added methanol (5 ml) and hydrochloric acid (4M, 3ml) and the mixture was heated at reflux for 60 h. The reaction mixturewas concentrated in vacuo and to the residue was added ethyl acetate (20ml) and water (20 ml). The organic phase was separated, washed withwater (2×20 ml) and brine (2×20 ml), dried (Na₂SO₄) and concentrated invacuo. The crude product was dissolved in a mixture of acetonitrile andwater (1:1:5 ml) and purified by automated preparative liquidchromatography (Gilson system, 150 mm×30 mm Phenomonex LUNA C18(2) 10 μmcolumn) using an acetonitrile:water gradient [60:40 to 95:5]. Theappropriate fractions were concentrated in vacuo to give the titledcompound (80 mg).

Experimental MH⁺ 549.9; expected 549.9

¹H-NMR (CDCl3): 3.41-3.47 (6H), 4.09-4.19 (2H), 7.88-7.94 (2H)

EXAMPLE 27N-{3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-1,1,1-trifluoro-N-methylmethanesulfonamide

To a solution of Example 20 (150 mg, 0.31 mmol) in tetrahydrofuran (5ml) was added dropwise tert-butyl nitrite (111 μl, 0.93 mmol). Thereaction mixture was then heated at 60° C. overnight. The reactionmixture was concentrated in vacuo and the residue was partitionedbetween ethyl acetate (20 ml) and water (20 ml). The organic layer wasseparated, washed with brine (20 ml), dried (Na₂SO₄) and concentrated invacuo. The residue was purified by column chromatography (silica, 10 g)eluting with dichloromethane/ethyl acetate [9:1]. The appropriatefractions were combined and concentrated to give the crude product. Thecrude product was dissolved in a mixture of acetonitrile, dimethylsulphoxide and water (4:5:1, 2 ml) and purified by automated preparativeliquid chromatography (Gilson system, 150 mm×30 mm Phenomonex LUNAC18(2) 10 μm column) using an acetonitrile:water gradient [60:40 to95:5]. The appropriate fractions were concentrated in vacuo to give thetitled compound (80 mg).

Experimental MH⁺ 467.0; expected 467.0

¹H-NMR (CDCl3): 3.65-3.65 (3H), 7.77-7.80 (2H), 7.80-7.82 (1H)

Similarly prepared was:

EXAMPLE 28N-{3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide

from the compound of Example 14 (1.00 g, 2.03 mmol) to give the titlecompound (855 mg).

Experimental MH⁺ 477.0; expected 477.0

¹H-NMR (CDCl3): 3.45-3.46 (6H), 7.75-7.78 (2H), 7.80-7.83 (1H)

EXAMPLE 29N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide

To a solution of Example 26 (310 mg, 0.56 mmol) in tetrahydrofuran (4ml) was added dropwise tert-butyl nitrite (200 μl, 1.69 mmol). Thereaction mixture was then heated at reflux for 16 h. The reactionmixture was concentrated in vacuo and the crude product was dissolved inacetonitrile (6 ml). The solution was passed through a 0.45μ filter andpurified by automated preparative liquid chromatography (Gilson system,150 mm×30 mm Phenomonex LUNA II 10μ C18 column) using anacetonitrile:water gradient [60:40 to 95:5]. The appropriate fractionswere concentrated in vacuo to give the titled compound (169 mg).

¹H-NMR (Acetone): 3.56-3.57 (6H), 8.28-8.35 (2H), 8.73-8.79 (1H)

EXAMPLE 30N-{3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}methanesulfonamide

To a solution of Example 28 (855 mg, 1.79 mmol) in tetrahydrofuran (20ml) was added potassium carbonate (617 mg, 4.48 mmol) in methanol (20ml), containing a few drops of water. The reaction mixture was thenstirred at room temperature for 2 h. The reaction mixture wasconcentrated in vacuo and to the residue was added hydrochloric acid(2M, 50 ml) and dichloromethane (100 ml). The organic phase was thenseparated, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified using an Isolute™ cartridge (silica, 20 g) with gradientelution, cyclohexane:ethyl acetate [1:0 to 1:1]. The appropriatefractions were combined and concentrated to give the titled compound(600 mg).

Experimental MH⁺ 399.0; expected 399.0

¹H-NMR (CDCl3): 3.08-3.10 (3H), 6.69-6.74 (1H), 7.73-7.78 (2H),7.80-7.84 (1H)

EXAMPLE 31N-{3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide

To a solution of sodium hydride (60% in oil, 14 mg, 0.35 mmol) in1-methyl-2-pyrrolidinone (6 ml) was added Example 30 (115 mg, 0.29mmol), followed by 2,2,2-trifluoroethyl trichloromethane sulphonate (185mg, 0.66 mmol), added via syringe. The reaction mixture was then heatedat 65° C. for 6 days. The reaction mixture was concentrated in vacuo andthe residue was purified using an Isolute™ cartridge (silica, 5 g) withgradient elution, dichloromethane:methanol [100:0 to 95:5]. Theappropriate fractions were combined and concentrated to give the titledcompound (41 mg).

¹H-NMR (CDCl3): 3.09-3.13 (3H), 4.27-4.34 (2H), 7.72-7.79 (2H),7.83-7.87 (1H)

EXAMPLE 32N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide

To a solution of Preparation 24 (80 mg, 0.13 mmol) in dioxane (2 ml) andmethanol (1 ml) was added hydrochloric acid (5N, 1 ml). The reactionmixture was then heated at 85° C. overnight. The reaction mixture wasconcentrated in vacuo and the residue was partitioned between water (5ml) and ethyl acetate (10 ml). The organic layer was separated, dried(MgSO₄) and concentrated in vacuo. The crude product was dissolved in amixture of acetonitrile and water and dimethyl (1:2, 1.6 ml) andpurified by automated preparative liquid chromatography (Gilson system,150 mm×30 mm Phenomonex LUNA C18(2) 10 μm column) using anacetonitrile:water gradient [55:45 to 95:5]. The appropriate fractionswere concentrated in vacuo to give the titled compound (43 mg).

Experimental MH⁺ 553.9; expected 554.0

¹H-NMR (CDCl3): 3.11-3.14 (3H), 4.12-4.30 (4H), 7.90-7.93 (2H)

Similarly prepared were:

Ex R1a R2 R4 From Prep 33 SF₅ CN 2-(1H-1,2,4-triazoly-yl)ethyl 42 34 ′CONH₂ Methylsulfonyl 37 35 OCF₃ CN ″ 21 36 SF₅ COCH₃ ″ 38 37 OCHF₂ CN ″22

EXAMPLE 33

Experimental MH⁺ 567.0; expected 567.0

¹H-NMR (CDCl3): 2.97-3.02 (3H), 4.05-4.18 (2H), 4.34-4.42 (2H),4.69-4.96 (2H), 7.88-7.91 (2H), 7.91-7.95 (1H), 8.34-8.39 (1H)

EXAMPLE 34

Experimental MH⁺ 567.9; expected 567.9

¹H-NMR (CDCl3): 3.43-3.47 (6H), 4.09-4.20 (2H), 5.36-5.44 (1H),6.58-6.65 (1H), 7.89-7.93 (2H)

EXAMPLE 35

Experimental MH⁺ 507.9; expected 508.0

¹H-NMR (CDCl3): 3.43-3.46 (6H), 4.08-4.12 (2H), 7.39-7.41 (2H)

EXAMPLE 36

Experimental MH⁺ 566.9; expected 566.9

¹H-NMR (CDCl3): 2.91-2.94 (3H), 3.10-3.13 (3H), 4.23-4.32 (2H),4.62-4.66 (2H), 6.65-6.69 (1H), 7.91-7.93 (2H)

EXAMPLE 37

Experimental MH⁺ 489.9; expected 490.0

¹H-NMR (CDCl3): 3.43-3.46 (6H), 4.09-4.13 (2H), 6.56-6.65 (1H),7.30-7.32 (2H)

EXAMPLE 38N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}methanesulfonamide

To a solution of Preparation 3 (121 mg, 0.23 mmol) in dioxane (4 ml) andmethanol (1 ml) was added hydrochloric acid (5N, 0.5 ml). The reactionmixture was then heated at 90° C. for 5 h. The reaction mixture wasconcentrated in vacuo and the residue was partitioned between ethylacetate (5 ml) and water (5 ml). The two layers were separated and theaqueous layer was extracted with ethyl acetate (2×5 ml). The combinedorganic phases were dried (MgSO₄) and concentrated in vacuo. The crudeproduct was dissolved in acetonitrile/dimethyl sulphoxide (1:1, 0.15 ml)and the solution was purified by automated preparative liquidchromatography (Gilson system, 150 mm×30 mm Phenomonex LUNA II 10 μm C18column) using an acetonitrile:water gradient [50:50 to 95:5]. Theappropriate fractions were concentrated in vacuo to give the titledcompound (63 mg).

Experimental MH⁺ 471.8; expected 472.0

¹H-NMR (CDCl3): 3.10-3.13 (3H), 4.25-4.31 (2H), 5.98-6.01 (1H),7.89-7.92 (2H)

EXAMPLE 39N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-{[1-(trifluoromethyl)cyclopropyl]methyl}methanesulfonamide

To a solution of Preparation 25 (155 mg, 0.24 mmol) in dioxane (3 ml)and methanol (1 ml) was added hydrochloric acid (5N, 0.5 ml). Thereaction mixture was then heated at 90° C. for 5 h. The reaction mixturewas concentrated in vacuo and the residue was partitioned between ethylacetate (6 ml) and water (6 ml). The organic phase was separated, dried(MgSO₄) and concentrated in vacuo. The crude product was dissolved inacetonitrile/dimethyl sulphoxide (1:1, 1.2 ml) and the solution waspurified by automated preparative liquid chromatography (Gilson system,150 mm×30 mm Phenomonex LUNA II 10 μm C18 column) using anacetonitrile:water gradient [60:40 to 95:5]. The appropriate fractionswere concentrated in vacuo to give the titled compound (72 mg).

Experimental MH⁺ 593.9; expected 594.0

¹H-NMR (CDCl3): 0.61-0.87 (2H), 0.99-1.06 (2H), 3.00-3.04 (3H),3.44-3.64 (1H), 4.14-4.38 (3H), 7.89-7.93 (2H)

EXAMPLE 40N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide

To a mixture of Example 38 (200 mg, 0.42 mmol) and ethanesulphonylchloride (0.11 ml, 1.20 mmol) in acetonitrile (12 ml) was addedpotassium carbonate (116 mg, 0.84 mmol). The reaction mixture was thenstirred at room temperature for 66 h. The reaction mixture wasconcentrated in vacuo and the residue was partitioned between water (20ml) and ethyl acetate (20 ml). The two layers were separated and theorganic layer was dried (MgSO₄) and concentrated in vacuo. The residuewas dissolved in acetonitrile/water (9:1, 4 ml) and the solution waspurified by automated preparative liquid chromatography (Gilson system,150 mm×30 mm Phenomonex LUNA II 10 μm C18 column) using anacetonitrile:water gradient [55:45 to 95:5]. The appropriate fractionswere concentrated in vacuo to give the titled compound (143 mg).

Experimental MH⁺ 563.9; expected 563.9

¹H-NMR (DMSO): 1.31-1.37 (3H), 3.45-3.49 (3H), 3.53-3.68 (2H), 6.74-6.81(2H), 8.40-8.44 (2H)

EXAMPLE 41 methyl5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl(methylsulfonyl)carbamate

To a solution of Example 15 (100 mg, 0.24 mmol) in acetone (4 ml) wasadded potassium carbonate (50 mg, 0.36 mmol) and methyl chloroformate(22.4 μl, 0.29 mmol). The reaction mixture was then heated at reflux for3 h. The reaction mixture was concentrated in vacuo and the residue waspartitioned between dichloromethane and water. The two layers wereseparated and the aqueous layer was extracted with dichloromethane (×3).The combined organic layers were then dried (MgSO₄) and concentrated invacuo. The crude product was dissolved in acetonitrile/water (4:1, 5 ml)and purified by automated preparative liquid chromatography (Gilsonsystem, 150 mm×30 mm Phenomenex LUNA C18(2) 10 μm column) using anacetonitrile:water gradient [50:50 to 95:5]. The appropriate fractionswere concentrated in vacuo to give the titled compound (90 mg).

Experimental MH⁺ 471.8; expected 472.0

¹H-NMR (CD3OD): 3.50-3.52 (3H), 3.85-3.86 (3H), 7.96-8.00 (2H)

EXAMPLE 42N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-methylmethanesulfonamide

To a mixture of Example 38 (200 mg, 0.42 mmol) and methyl iodide (52 μl,0.84 mmol) in acetonitrile (12 ml) was added potassium carbonate (116mg, 0.84 mmol). The reaction mixture was then stirred at roomtemperature for 66 h. The reaction mixture was partitioned betweenhydrochloric acid (1M) and ethyl acetate and the two layers wereseparated. The organic layer was washed with water, dried (MgSO₄) andconcentrated in vacuo. The residue was dissolved in acetonitrile/water(9:1, 8 ml) and the solution was purified by automated preparativeliquid chromatography (Gilson system, 150 mm×30 mm Phenomonex LUNA II 10μm C18 column) using an acetonitrile:water gradient [50:50 to 95:5]. Theappropriate fractions were concentrated in vacuo to give the titledcompound (54 mg).

Experimental MH⁺ 485.8; expected 486.0

¹H-NMR (DMSO): 2.99-3.03 (3H), 3.14-3.17 (3H), 6.40-6.46 (2H), 8.41-8.44(2H)

Similarly prepared from Example 38 were:

Ex R4 43 2-fluororoethyl 44 1,2,4-oxadiazol-3-ylmethyl 45aminocarbonylmethyl 46 1H-pyrazol-3-ylmethyl 472,2,3,3,3-pentafluoropropyl 48 2-pyrrolidin-1-ylethyl 492-morpholin-4-ylethyl

EXAMPLE 43

Experimental MH⁺ 517.9; expected 518.0

¹H-NMR (DMSO): 3.01-3.06 (3H), 3.61-3.93 (2H), 4.38-4.44 (1H), 4.50-4.56(1H), 6.44-6.51 (2H), 8.41-8.44 (2H)

EXAMPLE 44

Experimental MH⁺ 553.9; expected 554.0

¹H-NMR (DMSO): 3.12-3.14 (3H), 4.69-5.03 (2H), 6.54-6.59 (2H), 8.40-8.43(2H), 9.61-9.63 (1H)

EXAMPLE 45

Experimental MH⁺ 528.9; expected 529.0

¹H-NMR (DMSO): 2.28-2.31 (3H), 3.46-3.57 (2H), 4.00-4.01 (2H), 7.36-7.38(2H)

EXAMPLE 46

Experimental MH⁺ 552.0; expected 552.0

¹H-NMR (CDCl3): 3.15-3.20 (3H), 4.90-4.97 (2H), 5.43-5.57 (2H),6.40-6.43 (1H), 7.61-7.65 (1H), 7.87-7.90 (2H)

EXAMPLE 47

Experimental MH⁺ 603.9; expected 604.0

¹H-NMR (CDCl3): 3.10-3.14 (3H), 4.20-4.27 (2H), 7.90-7.93 (2H)

EXAMPLE 48

Experimental MH⁺ 569.0; expected 569.0

¹H-NMR (CDCl3): 1.67-1.83 (4H), 2.41-2.76 (6H), 3.08-3.15 (3H),3.51-3.99 (2H), 5.02-5.30 (2H), 7.88-7.91 (2H)

EXAMPLE 49

Experimental MH⁺ 585.0; expected 585.0

¹H-NMR (CDCl3): 2.41-2.55 (4H), 2.56-2.59 (4H), 3.09-3.14 (3H),3.61-3.73 (4H), 4.72-4.91 (2H), 7.88-7.91 (2H)

EXAMPLE 50N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanesulfonamide

To a mixture of Example 38 (200 mg, 0.42 mmol) and1-(N-methyl)-2-chloromethylimidazole (106 mg, 0.64 mmol) in acetonitrile(12 ml) was added potassium carbonate (116 mg, 0.84 mmol). The reactionmixture was then stirred at 40° C. for 18 h. To the reaction mixture wasadded water (6 ml) and ethyl acetate (10 ml). The two layers wereseparated and the aqueous layer was extracted with ethyl acetate (2×5ml). The combined organic phases were then dried (MgSO₄) andconcentrated in vacuo. The residue was dissolved in acetonitrile/water(3 ml) and the solution was purified by automated preparative liquidchromatography (Gilson system, 150×50 mm, LUNA II C18 10 μm column)using an acetonitrile:water gradient [45:55 to 95:5]. The appropriatefractions were concentrated to give the titled compound (98 mg).

Experimental MH^(÷) 565.9; expected 566.0

¹H-NMR (CDCl3): 2.88-2.91 (3H), 3.70-3.74 (3H), 4.80-5.03 (2H),6.09-6.18 (2H), 6.87-6.89 (1H), 6.92-6.95 (1H), 7.87-7.90 (2H)

EXAMPLE 51N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-[(5-methylisoxazol-3-yl)methyl]methanesulfonamide

To a mixture of Example 38 (200 mg, 0.42 mmol) and3-chloromethyl-5-methylisoxazole (84 mg, 0.64 mmol) in acetonitrile (12ml) was added potassium carbonate (116 mg, 0.84 mmol). The reactionmixture was then stirred at 40° C. for 18 h. To the reaction mixture wasadded water (6 ml) and ethyl acetate (10 ml). The two layers wereseparated and the aqueous layer was extracted with ethyl acetate (2×5ml). The combined organic phases were dried (MgSO₄) and concentrated invacuo to give a mixture of products. The residue was dissolved inacetonitrile/water (3.1 ml) and the solution was purified by automatedpreparative liquid chromatography (Gilson system, 150×50 mm, LUNA II C1810 μm column) using an acetonitrile:water gradient [50:50 to 95:5]. Theappropriate fractions were concentrated to give the titled compound (144mg).

Experimental MH⁺ 566.9; expected 567.0

¹H-NMR (CDCl3): 2.35-2.39 (3H), 3.11-3.15 (3H), 4.41-4.49 (2H),4.81-4.87 (2H), 6.01-6.04 (1H), 7.86-7.89 (2H)

EXAMPLE 52[{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}(methylsulfonyl)amino]methylpivalate

To a solution of Example 26 (200 mg, 0.36 mmol) and potassium carbonate(150 mg, 1.08 mmol) in acetonitrile (5 ml) was added chloromethylpivalate (0.16 ml, 1.08 mmol) and potassium iodide (10 mg). The reactionmixture was then heated at 50° C. for 16 h. The reaction mixture waspassed through a silica plug, eluting with methanol/dichloromethane[5:95]. The filtrate was then concentrated in vacuo. The residue wasdissolved in acetonitrile (1.5 ml) and purified by automated preparativeliquid chromatography (Gilson system, 150 mm×30 mm Phenomonex LUNAC18(2) 10 μm column) using an acetonitrile:water gradient [55:45 to95:5]. The appropriate fractions were concentrated in vacuo to give thetitled compound (24 mg).

Experimental MH⁺ 586.0; expected 586.0

¹H-NMR (CDCl3): 1.27-1.30 (9H), 3.21-3.23 (3H), 4.22-4.27 (2H),5.58-5.61 (2H), 7.92-7.95 (2H)

EXAMPLE 53N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-ethylmethanesulfonamide

To a mixture of Example 38 (200 mg, 0.42 mmol) and ethyl iodide (67 μl,0.84 mmol) in acetonitrile (12 ml) was added potassium carbonate (116mg, 0.84 mmol). The reaction mixture was then stirred at roomtemperature for 66 h. The reaction mixture was partitioned betweenhydrochloric acid (1M) and ethyl acetate and the two layers wereseparated. The organic layer was washed with water, dried (MgSO₄) andconcentrated in vacuo. The residue was dissolved in acetonitrile/water(9:1, 6 ml) and the solution was purified by automated preparativeliquid chromatography (Gilson system, 150 mm×30 mm Phenomonex LUNA II 10μm C18 column) using an acetonitrile:water gradient [60:40 to 95:5]. Theappropriate fractions were concentrated in vacuo to give the titledcompound (147 mg).

Experimental MH⁺ 499.9; expected 500.0

¹H-NMR (DMSO): 1.03-1.08 (3H), 2.99-3.02 (3H), 3.46-3.54 (2H), 6.41-6.45(2H), 8.41-8.44 (2H)

EXAMPLE 54N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-benzylmethanesulfonamide

To a mixture of Example 38 (200 mg, 0.42 mmol), potassium carbonate (116mg, 0.84 mmol) and potassium iodide (140 mg, 0.84 mmol) in acetonitrile(12 ml) was added benzyl bromide (100 μl, 0.84 mmol). The reactionmixture was then stirred at room temperature for 16 h. The reactionmixture was partitioned between hydrochloric acid (2M) anddichloromethane and the two layers were separated. The organic layer wasdried (MgSO₄) and concentrated in vacuo. The residue was dissolved inacetonitrile/water (4 ml) and the solution was purified by automatedpreparative liquid chromatography (Gilson system, 150×50 mm, LUNA II C1810 μm column) using an acetonitrile:water gradient [55:45 to 9:5]. Theappropriate fractions were concentrated to give the titled compound (285mg).

Experimental MH⁺ 561.9; expected 562.0

¹H-NMR (DMSO): 3.10-3.14 (3H), 4.46-4.82 (2H), 6.38-6.45 (2H), 7.22-7.28(5H), 8.34-8.41 (2H)

EXAMPLE 55N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(4-fluorobenzyl)methanesulfonamide

To a mixture of Example 38 (200 mg, 0.42 mmol), potassium carbonate (116mg, 0.84 mmol) and potassium iodide (140 mg, 0.84 mmol) in acetonitrile(12 ml) was added 4-fluorobenzyl bromide (105 μl, 0.84 mmol). Thereaction mixture was then stirred at room temperature for 16 h. Thereaction mixture was partitioned between hydrochloric acid (2M) anddichloromethane and the two layers were separated. The organic layer wasdried (MgSO₄) and concentrated in vacuo. The residue was dissolved inacetonitrile/water (3 ml) and the solution was purified by automatedpreparative liquid chromatography (Gilson system, 150×50 mm, LUNA II C1810 μm column) using an acetonitrile:water gradient [55:45 to 95:5]. Theappropriate fractions were concentrated to give the titled compound (269mg).

Experimental MH⁺ 580.0; expected 580.0

¹H-NMR (DMSO): 3.10-3.14 (3H), 4.43-4.81 (2H), 6.38-6.45 (2H), 7.08-7.14(2H), 7.24-7.29 (2H), 8.36-8.41 (2H)

EXAMPLE 56N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-1-(methylsulfonyl)ethanesulfonamide

To a solution of Example 9 (90 mg, 0.18 mmol) in acetone (3 ml) wasadded methyl iodide (11 μl, 0.18 mmol) and potassium carbonate (20 mg).The reaction mixture was then stirred at room temperature overnight. Thereaction mixture was concentrated in vacuo and the residue waspartitioned between ethyl acetate (3 ml) and water (3 ml). The organicphase was then separated, dried and concentrated in vacuo. The crudeproduct was dissolved in a mixture of acetonitrile (0.5 ml) and dimethylsulphoxide (0.3 ml) and purified by automated preparative liquidchromatography (Gilson system, 150 mm×30 mm Phenomonex LUNA II C18 10μcolumn) using an acetonitrile:water gradient [10:90 to 98:2]. Theappropriate fractions were concentrated in vacuo to give the titledcompound (21 mg).

¹H-NMR (DMSO): 1.55-1.60 (3H), 3.21-3.22 (3H), 5.20-5.26 (1H), 6.38-6.49(2H), 8.22-8.24 (2H)

EXAMPLE 57N-{5-amino-1-[2-chloro-4-pentafluorothio-phenyl]-3-cyano-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide

To a solution of Example 26 (50 mg, 0.09 mmol) in tetrahydrofuran (10ml), under nitrogen, was added ethylmagnesium bromide (3M intetrahydrofuran, 0.09 ml, 0.27 mmol). The reaction mixture was thenstirred under nitrogen, at room temperature, overnight. The reactionmixture was quenched by addition of methanol and the mixture wasconcentrated in vacuo. The residue was partitioned betweendichloromethane and water and the organic phase was separated, dried andconcentrated in vacuo. The residue was dissolved in acetonitrile/water(1.5 ml) and the solution was purified by automated preparative liquidchromatography (Gilson system, 150×30 mm, LUNA II C18 10 μm column)using an acetonitrile:water gradient [45:55 to 98:2]. The appropriatefractions were concentrated to give the titled compound (3 mg).

Experimental MH⁺ 515.9; expected 516.0

¹H-NMR (DMSO): 3.50-3.54 (6H), 6.70-6.74 (2H), 7.87-7.91 (1H), 8.08-8.12(1H), 8.39-8.41 (1H)

Alternative Synthesis

To a solution of Preparation 28 (680 mg, 1.89 mmol) in dichloromethane(20 ml) was added triethylamine (1.52 ml, 7.56 mmol), followed bymethanesulphonyl chloride (870 mg, 7.56 mmol). The reaction mixture wasthen stirred overnight at room temperature. The reaction mixture waswashed with hydrochloric acid (1N, 50 ml) and the organic phase wasseparated, dried (MgSO₄) and concentrated in vacuo. The residue wasdissolved in acetonitrile/water (2 ml) and the solution was purified byautomated preparative liquid chromatography (Gilson system, 150 mm×30 mmLUNA II C18 10 μm column) using an acetonitrile:water gradient [50:50 to95:5]. The appropriate fractions were combined and concentrated to givethe titled compound (37 mg).

Experimental MH⁺ 514.1; expected 514.0

¹H-NMR (DMSO): 3.50-3.54 (6H), 6.70-6.74 (2H), 7.87-7.91 (1H), 8.08-8.12(1H), 8.39-8.41 (1H)

EXAMPLE 585-amino-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-(1,1-dioxido-1,2-thiazinan-2-yl)-1H-pyrazole-3-carbonitrile

To a solution of Preparation 43 (350 mg, 0.89 mmol) in pyridine (5 ml)was added 4-chlorobutane-1-sulfonyl chloride (WO 2004050619 A1, 254 mg,1.33 mmol). The reaction mixture was then stirred at room temperaturefor 18 h. The reaction mixture was partitioned between dichloromethane(20 ml) and water (20 ml) and the organic phase was separated, dried andconcentrated in vacuo. To the residue was added N,N-dimethylformamide (5ml) and potassium carbonate (123 mg, 0.89 mmol). The mixture was thenheated at 85° for 60 h. The reaction mixture was concentrated in vacuoand the residue was partitioned between dichloromethane (25 ml) andwater (25 ml). The organic phase was separated, dried and concentratedin vacuo. The residue was dissolved in acetonitrile/water (9:1, 2 ml)and the solution was purified by automated preparative liquidchromatography (Gilson system, 150×30 mm, LUNA II C18 10 μm column)using an acetonitrile:water gradient [50:50 to 9:5]. The appropriatefractions were concentrated to give the titled compound (28 mg).

Experimental MH⁺ 511.9; expected 512.0

¹H-NMR (CDCl3): 1.98-2.02 (2H), 2.30-2.36 (2H), 3.26-3.30 (2H),3.73-3.77 (2H), 4.13-4.22 (2H), 7.87-7.90 (2H)

EXAMPLE 59N-{5-(benzylamino)-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide

To a solution of Preparation 44(120 mg, 0.18 mmol) in ethanol (5 ml), at0° C., was added sodium borohydride (14 mg, 0.36 mmol). The reactionmixture was then allowed to warm to room temperature over 2 h. To thereaction mixture was added hydrochloric acid (2N, 5 ml), followed bywater (10 ml) and ethyl acetate (15 ml). The two layers were separatedand the aqueous layer was extracted with ethyl acetate (3×15 ml). Thecombined organic phases were then washed with brine, dried (MgSO₄) andconcentrated in vacuo. The residue was dissolved inacetonitrile/dimethyl sulphoxide (8:2, 2 ml) and the solution waspurified by automated preparative liquid chromatography (Gilson system,150×30 mm, LUNA II C18 10 μm column) using an acetonitrile:watergradient [60:40 to 98:2]. The appropriate fractions were concentrated togive the titled compound (45 mg).

Experimental MH⁺ 639.9; expected 640.0

¹H-NMR (DMSO): 3.36-3.38 (6H), 4.41-4.44 (2H), 7.13-7.29 (6H), 8.35-8.36(2H)

EXAMPLE 60N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-[(methylsulfonyl)(2,2,2-trifluoroethyl)amino]-1H-pyrazol-5-yl}-2-methoxyacetamide

To a solution of Example 32 (200 mg, 0.36 mmol) in acetonitrile (5 ml),at 0° C., was added methoxyacetyl chloride (587 mg, 5.4 mmol) andpyridine (142 mg, 1.80 mmol). The reaction mixture was then heated atreflux for 36 h. The reaction mixture was concentrated in vacuo and theresidue was partitioned between ethyl acetate and water. The organicphase was separated, washed with brine, dried (MgSO₄) and concentratedin vacuo. The residue was dissolved in acetonitrile (3 ml) and thesolution was purified by automated preparative liquid chromatography(Gilson system, 150×30 mm, LUNA II C18 10 μm column) using anacetonitrile:water gradient [60:40 to 98:2]. The appropriate fractionswere concentrated to give the titled compound (164 mg).

Experimental MH⁺ 625.9; expected 626.0

¹H-NMR (CDCl3): 3.12-3.15 (3H), 3.41-3.44 (3H), 3.82-3.86 (2H),4.20-4.30 (2H), 7.83-7.86 (2H), 8.74-8.79 (1H)

EXAMPLE 61 ethyl4-[bis(methylsulfonyl)amino]-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-5-ylimidoformate

To a solution of Example 26 (200 mg, 0.36 mmol) in triethyl orthoformate(8 ml) was added hydrochloric acid (concentrated, 2 ml). The reactionmixture was then heated at 60° C. for 2 h. The reaction mixture wasconcentrated in vacuo and the residue was washed with toluene. Theresidue was dissolved in acetonitrile (2 ml) and the solution waspurified by automated preparative liquid chromatography (Gilson system,150×30 mm, LUNA II C18 10 μm column) using an acetonitrile:watergradient [55:45 to 95:5]. The appropriate fractions were concentrated togive the titled compound (104 mg).

Experimental MH⁺ 605.9; expected 606.0

¹H-NMR (CDCl3): 1.19-1.24 (3H), 3.41-3.45 (6H), 4.09-4.16 (2H),7.84-7.87 (2H), 8.23-8.25 (1H)

EXAMPLE 62N-{3-cyano-5-[(cyclopropylmethyl)amino]-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}methanesulfonamide

To a suspension of Example 26 (100 mg, 0.18 mmol) in toluene (4 ml) wasadded molecular sieves (400 mg), cyclopropanecarboxaldehyde (40 μl, 0.54mmol) and p-toluenesulphonic (catalytic amount). The reaction mixturewas heated at 90° C. for 6 h, cooled and concentrated in vacuo. To asolution of the residue in ethanol (4 ml), at 0° C., was added sodiumborohydride (16 mg, 0.36 mmol). The reaction mixture was allowed to warmto room temperature and stirred overnight. The residue was dissolved inacetonitrile/water (9:1, 1.5 ml) and purified by automated preparativeliquid chromatography (Gilson system, 150 mm×30 mm Phenomonex LUNAC18(2) 10 μm column) using an acetonitrile:water gradient [50:50 to95:5]. The appropriate fractions were concentrated in vacuo to give amixture of the titled compound (27 mg) and the bis-sulphonated compound.

Experimental MH⁺ 526.0; expected 526.0

¹H-NMR (CDCl3): 0.09-0.13 (2H), 0.44-0.50 (2H), 0.85-0.93 (1H),2.78-2.82 (2H), 3.12-3.16 (3H), 5.95-5.99 (1H), 7.87-7.90 (2H)

EXAMPLE 63N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-[(methylsulfonyl)(2,2,2-trifluoroethyl)amino]-1H-pyrazol-5-yl}acetamide

To a solution of Example 32 (50 mg, 0.09 mmol) and4-dimethylaminopyridine (122 mg, 1.0 mmol) in dichloromethane (0.5 ml)was added acetic anhydride (0.11 ml, 1.2 mmol) and N,N-dimethylformamide(1 drop). The reaction mixture was then stirred at room temperature for4 h. The reaction mixture was partitioned between hydrochloric acid (1M)and dichloromethane and the organic phase was separated, washed withwater, dried (MgSO₄) and concentrated in vacuo. The residue wasdissolved in acetonitrile (1.5 ml) and purified by automated preparativeliquid chromatography (Gilson system, 150 mm×30 mm Phenomonex LUNAC18(2) 10 μm column) using an acetonitrile:water gradient [55:45 to95:5]. The appropriate fractions were concentrated in vacuo to give thetitled compound (34 mg).

Experimental MH⁺ 596.0; expected 596.0

¹H-NMR (DMSO): 1.94-1.98 (3H), 3.16-3.21 (3H), 4.44-4.56 (2H), 8.49-8.53(2H), 10.38-10.42 (1H)

EXAMPLE 64N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-methoxy-1H-pyrazol-4-yl}methanesulfonamide

A mixture of Example 66 (140 mg, 0.25 mmol) and sodium hydroxide (1M,0.5 ml, 0.5 mmol) in tetrahydrofuran (5 ml) was stirred at roomtemperature for 60 h. To the reaction mixture was added hydrochloricacid (2N, 10 ml) and the mixture was extracted with ethyl acetate (2×10ml). The combined extracts were dried (MgSO₄) and concentrated in vacuo.The residue was dissolved in acetonitrile (1.5 ml) and purified byautomated preparative liquid chromatography (Gilson system, 150 mm×30 mmPhenomonex LUNA C18(2) 10 μm column) using an acetonitrile:watergradient [50:50 to 95:5]. The appropriate fractions were concentrated invacuo to give the titled compound (67 mg).

Experimental MH⁺ 486.8; expected 487.0

¹H-NMR (CDCl3): 3.19-3.22 (3H), 4.22-4.25 (3H), 5.90-5.94 (1H),7.84-7.88 (2H)

EXAMPLE 65N-[3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-(methylamino)-1H-pyrazol-4-yl]-N-(methylsulfonyl)methanesulfonamide

To a mixture of Preparation 30 (35 mg, 0.10 mmol) and triethylamine (28μl, 0.20 mmol) in dichloromethane (1 ml), at 0° C., was added dropwisemethanesulphonyl chloride (16 μl, 0.20 mmol). The reaction mixture wasallowed to warm to room temperature and stirred for 2 h. To the reactionmixture was added dichloromethane (5 ml) and the solution was washedwith hydrochloric acid (2N, 5 ml) and brine (5 ml), dried (MgSO₄) andconcentrated in vacuo. The residue was dissolved inacetonitrile/dimethyl sulphoxide (1:1, 1 ml) and the solution waspurified by automated preparative liquid chromatography (Gilson system,250×21.2 mm, LUNA II C18 5 μm column) using an acetonitrile:watergradient [45:55 to 98:2]. The appropriate fractions were concentrated togive the titled compound (7 mg).

Experimental MH⁺ 505.9; expected 506.0

¹H-NMR (CDCl3): 2.82-2.86 (3H), 3.46-3.49 (6H), 3.78-3.86 (1H),7.75-7.77 (2H)

Similarly prepared were:

Ex R2 R5 From prep 66 CN OMe 29 67 CN

33 68 ″ [2-(dimethylamino)ethyl]amino 32 69 ″(2-pyrrolidin-1-ylethyl)amino 34 70 ″ (2-morpholin-4-ylethyl)amino 31 71″ (2-piperidin-1-ylethyl)amino 36 72 cyclopropyl NH₂ 26

EXAMPLE 66

¹H-NMR (CDCl3): 3.48-3.52 (6H), 4.07-4.10 (3H), 7.87-7.90 (2H)

EXAMPLE 67

Experimental MH⁺ 605.0; expected 605.0

¹H-NMR (CDCl3): 2.77-2.84 (3H), 2.99-3.05 (3H), 3.34-3.43 (6H),7.78-7.84 (2H), 8.02-8.07 (1H)

EXAMPLE 68

Experimental MH⁺ 621.0; expected 621.0

¹H-NMR (CDCl3): 2.74-2.79 (6H), 3.20-3.24 (2H), 3.47-3.51 (6H),3.75-3.81 (2H), 7.11-7.17 (1H), 7.85-7.87 (2H)

EXAMPLE 69

MS (ES): M/Z [MH+] 647.0; expected mass for C18H21Cl2F5N₆O4S3+H is 647.0

¹H-NMR (DMSO): 1.72-1.84 (2H), 1.86-1.97 (2H), 2.85-2.95 (2H), 3.15-3.22(2H), 3.36-3.45 (2H), 3.56-3.64 (8H), 6.88-6.93 (1H), 8.43-8.46 (2H)

EXAMPLE 70

MS (ES): M/Z [MH+] 663.1; expected mass for C18H21Cl2F5N6O5S3+H is 663.0

¹H-NMR (CDCl3): 2.84-2.95 (2H), 3.22-3.28 (2H), 3.37-3.44 (2H),3.47-3.51 (6H), 3.80-3.89 (4H), 3.91-4.00 (2H), 6.56-6.68 (1H),7.85-7.88 (2H)

EXAMPLE 71

MS (ES): M/Z [MH+] 661.0; expected mass for C19H23Cl2F5N6O4S3+H is 661.0

¹H-NMR (DMSO): 1.31-1.40 (1H), 1.65-1.71 (1H), 1.72-1.79 (4H), 2.80-2.90(2H), 3.11-3.17 (2H), 3.27-3.31 (2H), 3.64-3.67 (6H), 3.67-3.73 (2H),7.03-7.07 (1H), 8.46-8.48 (2H)

EXAMPLE 72

Experimental MH⁺ 565.0; expected 565.0

¹H-NMR (CDCl3): 0.90-0.98 (4H), 1.83-1.91 (1H), 3.41-3.45 (6H),3.75-3.89 (2H), 7.82-7.85 (2H)

EXAMPLE 73N-{5-amino-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}methanesulfonamide

To a mixture of Preparation 27 (177 mg, 0.33 mmol) and triethylamine(115 μl, 0.83 mmol) in dichloromethane (3 ml) and tetrahydrofuran (1 ml)was added methanesulphonyl chloride (53 μl, 0.83 mmol). The reactionmixture was then stirred at room temperature for 16 h. The reactionmixture was washed with hydrochloric acid (1M) and water, dried (MgSO₄)and concentrated in vacuo to give the crude product. The residue wasdissolved in acetonitrile/water (1.2 ml) and the solution was purifiedby automated preparative liquid chromatography (Gilson system, 150×50mm, LUNA II C18 10 μm column) using an acetonitrile:water gradient[35:65 to 95:5]. The appropriate fractions were concentrated to give thetitled compound (74 mg).

¹H-NMR (CDCl3): 2.99-3.03 (3H), 3.44-3.47 (2H), 5.74-5.83 (1H),7.53-7.56 (1H), 7.86-7.89 (2H)

Similarly prepared was:

EXAMPLE 74N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-[(pyridin-4-ylmethyl)amino]-1H-pyrazol-4-yl}methanesulfonamide

from the compound of Preparation 35 (257 mg, 0.53 mmol) andmethanesulphonyl chloride (0.12 ml, 1.59 mmol) to give the titlecompound (13 mg).

Experimental MH⁺ 562.9; expected 563.0

¹H-NMR (DMSO): 3.03-3.06 (3H), 4.63-4.67 (2H), 7.06-7.11 (1H), 7.40-7.44(2H), 8.47-8.49 (2H), 8.59-8.63 (2H), 9.10-9.13 (1H)

EXAMPLE 75 tert-butyl({5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}amino)sulfonylcarbamate

A mixture of tert-butanol (0.27 ml, 2.87 mmol) and chlorosulphonylisocyanate (0.25 ml, 2.87 mmol) in dichloromethane (12 ml) was stirredat room temperature for 1 h, before the dropwise addition of Preparation43 (1.13 g, 2.87 mmol) and triethylamine (0.6 ml, 4.31 mmol) indichloromethane (12 ml). The reaction mixture was then stirred at roomtemperature for 2 h. The reaction mixture was partitioned betweenhydrochloric acid (0.5M) and dichloromethane and the organic phase wasseparated, washed with water, dried (MgSO₄) and concentrated in vacuo.The residue was purified by column chromatography, eluting with ethylacetate/cyclohexane [1:9]. The appropriate fractions were combined andconcentrated to give the titled compound (0.62 g).

Experimental MH⁺ 573.0; expected 573.0

¹H-NMR (DMSO): 1.36-1.41 (9H), 5.83-5.94 (2H), 8.39-8.42 (2H), 9.57-9.60(1H), 11.07-11.11 (1H)

EXAMPLE 76N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2-pyridin-4-ylethyl)methanesulfonamide

A mixture of Example 38 (200 mg, 0.42 mmol), 4-(2-hydroxyethyl)pyridine(52 mg, 0.42 mmol) and triphenylphosphine (167 mg, 0.64 mmol) inanhydrous tetrahydrofuran (5 ml) was cooled to 0° C. and diethylazodicarboxylate (0.1 ml, 0.64 mmol) was added. The reaction mixture waswarmed to room temperature and stirred under nitrogen overnight. Thereaction mixture was concentrated in vacuo and the residue waspartitioned between dichloromethane and water. The organic phase wasthen separated, dried and concentrated in vacuo. The residue wasdissolved in acetonitrile/water (4 ml) and the solution was purified byautomated preparative liquid chromatography (Gilson system, 150×30 mm,LUNA II C18 10 μm column) using an acetonitrile:0.1% trifluoroaceticacid gradient [35:65 to 95:5]. The appropriate fractions wereconcentrated to give the titled compound (55 mg).

Experimental MH⁺ 577.0; expected 577.0

¹H-NMR (CDCl3): 2.99-3.04 (3H), 3.11-3.18 (2H), 4.12-4.17 (2H),4.19-4.41 (2H), 7.62-7.69 (2H), 7.86-7.89 (2H), 8.59-8.67 (2H)

Similarly prepared were:

EXAMPLE 77N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(pyrazin-2-ylmethyl)methanesulfonamide

from the compound of Example 38 (200 mg, 0.42 mmol) andpyrazin-2-ylmethanol (47 mg, 0.42 mmol) to give the title compound (100mg). Experimental MH⁺ 564.0; expected 564.0

¹H-NMR (CDCl3): 3.19-3.23 (3H), 4.98-5.06 (2H), 7.87-7.91 (2H),8.52-8.57 (2H), 8.61-8.66 (1H)

EXAMPLE 78N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-[(6-aminopyridin-3-yl)methyl]methanesulfonamide

from the compound of Example 38 (200 mg, 0.42 mmol) and(6-aminopyridin-3-yl)methanol (WO 2003000682 A1, 53 mg, 0.43 mmol) togive the title compound (82 mg).

Experimental MH⁺ 578.0; expected 578.0

¹H-NMR (DMSO): 3.15-3.21 (3H), 4.34-4.47 (1H), 4.61-4.75 (1H), 6.48-6.57(2H), 6.91-6.95 (1H), 7.69-7.73 (1H), 7.78-7.83 (1H), 7.91-8.10 (2H),8.41-8.47 (2H)

EXAMPLE 79N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-2-oxo-N-(2,2,2-trifluoroethyl)propane-1-sulfonamide

To a solution of Preparation 47 (192 mg, 0.29 mmol) in tetrahydrofuran(2 ml), at −30° C., was added dropwise isopropylmagnesium chloride (2Min tetrahydrofuran, 0.16 ml, 0.32 mmol). After 30 min, acetyl chloride(41 μl, 0.58 mmol) was added via syringe and the reaction mixture wasallowed to warm to room temperature and stirred for 2 h. To the reactionmixture was added hydrochloric acid (2N, 10 ml) and the mixture wasextracted with ethyl acetate (2×10 ml). The combined extracts were dried(MgSO₄) and concentrated in vacuo to give a mixture of products. Theresidue was dissolved in acetonitrile (1 ml) and purified by automatedpreparative liquid chromatography (Gilson system, 250 mm×30 mmPhenomonex LUNA C18(2) 10 μm column) using an acetonitrile:0.1%trifluoroacetic acid gradient [60:40 to 98:2]. The appropriate fractionswere concentrated in vacuo to give a mixture of the titled compound (15mg) and other products.

Experimental MH⁺ 580.9; expected 581.0

¹H-NMR (CDCl3): 2.36-2.39 (3H), 4.17-4.20 (2H), 4.30-4.38 (2H),7.88-7.92 (3H)

EXAMPLE 80 hydrochloride salt ofN-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[3-(dimethylamino)ethyl]amino}-1H-pyrazol-4-yl)-N-(2,2,2-trifluoroethyl)methanesulfonamide

To a mixture of Preparation 40 (505 mg, 0.91 mmol) and potassiumcarbonate (800 mg, 5.80 mmol) in acetonitrile (10 ml) was added dropwise2,2,2-trifluoroethyl trichloromethane sulphonate (0.30 ml, 1.83 mmol).The reaction mixture was then heated at 40° C. for 19 h. The reactionmixture was partitioned between ethyl acetate and water and the twolayers were separated. The aqueous layer was extracted with ethylacetate and the combined organic phases were washed with saturatedsodium hydrogencarbonate solution and brine, dried (MgSO₄) andconcentrated in vacuo. The residue was dissolved in acetonitrile (2 ml)and the solution was purified by automated preparative liquidchromatography (Gilson system, 150×30 mm, LUNA II C18 10 μm column)using an acetonitrile:0.1% trifluoroacetic acid gradient [40:60 to95:5]. The appropriate fractions were concentrated to give thetrifluoroacetate salt of the desired compound. A solution of thetrifluoroacetate salt in dichloromethane (10 ml) was washed withsaturated aqueous sodium hydrogencarbonate solution (10 ml) and brine,dried (MgSO₄) and concentrated in vacuo. To a solution of the residue indiethyl ether (5 ml) and methanol (1 drop) was added hydrogen chloridein diethyl ether (2 ml). The reaction mixture was then stirred for 5 minand concentrated in vacuo. To the residue was added acetonitrile (3 ml)and water (0.5 ml) and the solution was freeze-dried to give the titledcompound (35 mg).

Experimental MH⁺ 639.1; expected 639.0

¹H-NMR (DMSO): 2.62-2.65 (6H), 2.95-3.11 (2H), 3.29-3.30 (4H), 3.35-3.37(3H), 4.55-4.63 (2H), 8.52-8.54 (2H)

EXAMPLE 81 hydrochloride salt ofN-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-[(2-piperidin-1-ylethyl)amino]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide

from the compound of Preparation 41 (420 mg, 0.72 mmol) and2,2,2-trifluoroethyl trichloromethane sulphonate (0.30 ml, 1.83 mmol) togive the title compound (175 mg).

MS (ES): M/Z [MH+] 665.1; expected mass for C20H22Cl2F8N6O2S2+H is 665.1

¹H-NMR (DMSO): 1.63-1.74 (4H), 2.72-2.85 (2H), 3.01-3.08 (2H), 3.21-3.28(4H), 3.30-3.33 (3H), 3.47-3.77 (2H), 4.43-4.52 (2H), 6.74-6.79 (1H),8.41-8.45 (2H)

EXAMPLE 82N-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}sulfamide

To a solution of Example 75 (150 mg, 0.26 mmol) in dichloromethane (2.4ml), at 0° C., was added trifluoroacetic acid (0.6 ml, 7.79 mmol). Thereaction mixture was then stirred at room temperature for 2.5 h. Thereaction mixture was concentrated in vacuo and the residue was dissolvedin acetonitrile/water (2 ml). The solution was purified by automatedpreparative liquid chromatography (Gilson system, 150×30 mm, LUNA II C1810 μm column) using an acetonitrile:water gradient [40:60 to 95:5]. Theappropriate fractions were concentrated to give the titled compound (77mg).

Experimental MH⁺ 472.8; expected 473.0

¹H-NMR (DMSO): 6.02-6.07 (2H), 6.81-6.85 (2H), 8.41-8.44 (2H), 8.51-8.57(1H)

EXAMPLE 83N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-4-fluoro-N-(methylsulfonyl)benzenesulfonamide

To a mixture of Example 15 (200 mg, 0.48 mmol), 4-dimethylaminopyridine(20 mg) and pyridine (0.2 ml) in dichloromethane (4 ml) was added4-fluorobenzenesulphonyl chloride (93 mg, 0.48 mmol). The reactionmixture was then stirred overnight at room temperature. The reactionmixture was partitioned between ethyl acetate (25 ml) and water (25 ml)and the two layers were separated. The organic layer was then dried(Na₂SO₄) and concentrated in vacuo The residue was purified using anIsolute™ cartridge (silica, 25 g) with gradient elution, ethylacetate:cyclohexane [15:85 to 1:1]. The appropriate fractions werecombined and concentrated to give the titled compound (55 mg).

Experimental MH⁺ 571.9; expected 572.0

¹H-NMR (DMSO): 3.69-3.75 (3H), 6.63-6.70 (2H), 7.51-7.57 (2H), 7.89-7.95(2H), 8.19-8.29 (2H)

Similarly prepared was:

EXAMPLE 84N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2,4-difluoro-N-(methylsulfonyl)benzenesulfonamide

from the compound of Example 15 (200 mg, 0.48 mmol) and2,4-difluorobenzenesulphonyl chloride (102 mg, 0.48 mmol) to give thetitle compound (50 mg).

Experimental MH^(÷) 589.9; expected 590.0

¹H-NMR (CDCl3): 3.58-3.60 (3H), 4.26-4.34 (2H), 7.00-7.10 (2H),7.75-7.82 (2H), 7.92-8.01 (1H)

EXAMPLE 85 methyl3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-[(methylsulfonyl)(2,2,2-trifluoroethyl)amino]-1H-pyrazol-5-ylcarbamate

To a solution ofN-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide(200 mg, 0.6 mmol), pyridine (73 μl, 0.90 mmol) and 3A molecular sieves(0.2 g) in toluene/dichloromethane (2:3, 3.6 ml), at 0° C., was addedphosgene (20% in toluene, 1.7M, 2 ml). After stirring for 1 h at 0° C.,methanol (2 ml) was added and the reaction mixture was allowed to warmto room temperature. The reaction mixture was concentrated in vacuo togive the crude product. The crude product was dissolved inacetonitrile/dimethyl sulphoxide (1 ml) and the solution was purified byautomated preparative liquid chromatography (Gilson system, 250×30 mm,LUNA II C18 10 μm column) using an acetonitrile:0.1% trifluoroaceticacid gradient [55:45 to 95:5]. The appropriate fractions wereconcentrated to give the titled compound (12 mg).

Experimental MH⁺ 612.1; expected 612.0

¹H-NMR (DMSO): 3.18-3.22 (3H), 3.54-3.58 (3H), 4.44-4.60 (2H), 8.51-8.55(2H), 10.30-10.35 (1H)

Similarly prepared were:

EXAMPLE 86N-{5-({[(2-aminoethyl)amino]carbonyl}amino)-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide

fromN-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide(100 mg, 0.18 mmol) and ethylene diamine (1 ml) to give the titlecompound (12 mg).

Experimental MH⁺ 640.0; expected 640.0

¹H-NMR (CD3OD): 3.23-3.26 (3H), 3.75-3.81 (2H), 3.94-3.99 (2H),4.11-4.14 (2H), 8.20-8.23 (2H)

EXAMPLE 87 trifluoroacetate salt ofN-{5-[(2-azetidin-1-ylethyl)amino]-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide

To a mixture of Preparation 48 (120 mg, 0.20 mmol), sodiumtriacetoxyborohydride (43 mg, 0.20 mmol) and azetidine (14 μl, 0.20mmol) in dichloromethane (2 ml) was added acetic acid (11 μl, 0.20mmol). The reaction mixture was then stirred at room temperature for 72h. The reaction mixture was partitioned between aqueous sodiumhydrogencarbonate solution and ethyl acetate. The organic layer wasseparated, dried (MgSO₄) and concentrated in vacuo. The residue wasdissolved in acetonitrile/water (1 ml) and the solution was purified byautomated preparative liquid chromatography (Gilson system, 150×30 mm,LUNA II C18 10 μm column) using an acetonitrile:0.2% trifluoroaceticacid gradient [40:60 to 95:5]. The appropriate fractions wereconcentrated to give the titled compound (28 mg).

Experimental MH⁺ 637.1; expected 637.0

¹H-NMR (CDCl3): 2.30-2.42 (1H), 2.58-2.71 (1H), 3.18-3.22 (3H),3.35-3.49 (2H), 3.74-3.84 (1H), 3.85-4.00 (2H), 4.09-4.19 (1H),4.21-4.33 (3H), 4.40-4.54 (1H), 6.54-6.63 (1H), 7.82-7.88 (2H)

EXAMPLE 88N-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(2,4-dihydroxyphenyl)methylene]amino}-1H-pyrazol-4-yl)-N-(2,2,2-trifluoroethyl)methanesulfonamide

A mixture ofN-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide(500 mg, 0.9 mmol), 2,3-dihydroxybenzaldehyde (248 mg, 1.8 mmol),molecular sieves and p-toluenesulphonic acid (17 mg) in toluene (15 ml)was heated at reflux overnight. The reaction mixture was concentrated invacuo and the residue was washed with water, ethyl acetate and brine,dried (MgSO₄) and concentrated in vacuo. The residue was dissolved inacetonitrile/dimethyl sulphoxide (1 ml) and the solution was purified byautomated preparative liquid chromatography (Gilson system, 150×50 mm,LUNA II C18 10 μm column) using an acetonitrile:water gradient [65:35 to95:5]. The appropriate fractions were concentrated to give the titledcompound (200 mg).

Experimental MH⁺ 673.9; expected 674.0

¹H-NMR (DMSO): 3.29-3.31 (3H), 4.49-4.57 (2H), 6.13-6.17 (1H), 6.25-6.29(1H), 7.34-7.39 (1H), 8.52-8.54 (2H), 8.87-8.90 (1H)

EXAMPLE 89N-{5-chloro-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide

To a mixture ofN-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide(250 mg, 0.45 mmol) and copper (II) chloride (303 mg, 2.25 mmol) inacetonitrile (5 ml) was added tert-butyl nitrite (102 μl, 0.68 mmol) inacetonitrile (1 ml). The reaction mixture was then stirred at roomtemperature for 3 h. The reaction mixture was concentrated in vacuo andthe residue was partitioned between ethyl acetate (10 ml) and water (10ml). The two layers were separated and the aqueous layer was extractedwith ethyl acetate (10 ml). The combined organic phases were then dried(MgSO₄) and concentrated in vacuo. The residue was dissolved inacetonitrile (1 ml) and the solution was purified by automatedpreparative liquid chromatography (Gilson system, 150×30 mm, LUNA II C1810 μm column) using an acetonitrile:water gradient [60:40 to 95:5]. Theappropriate fractions were concentrated to give the titled compound (58mg).

¹H-NMR (CDCl3): 3.21-3.25 (3H), 4.22-4.30 (2H), 7.90-7.93 (2H)

EXAMPLE 90N-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[3-(dimethylamino)ethyl]amino}-1H-pyrazol-4-yl)-N-(methylsulfonyl)methanesulfonamide

To a mixture of Preparation 33 (550 mg, 1.0 mmol) and triethylamine(0.33 ml, 2.3 mmol) in dichloromethane (15 ml), at 0° C., was addeddropwise methanesulphonyl chloride (0.19 ml, 2.3 mmol). The reactionmixture was allowed to warm to room temperature and stirred for 16 h. Tothe reaction mixture was added water (10 ml) and the two layers wereseparated. The aqueous layer was extracted with dichloromethane (2×20ml) and the combined organic phases were washed with brine, dried(MgSO₄) and concentrated in vacuo to the titled compound (600 mg).

Experimental MH⁺ 635.0; expected 635.0

The following Preparations illustrate the synthesis of certainintermediates used in the preparation of the preceding Examples.

Preparation 1N-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)-3,4-difluorobenzenesulfonamide

To a solution of Preparation 51 (200 mg, 0.51 mmol) in dichloromethane(4 ml) was added 4-dimethylaminopyridine (20 mg), pyridine (0.2 ml) and3,4-difluorobenzenesulphonyl chloride (163 mg, 0.77 mmol). The reactionmixture was then stirred at room temperature overnight. The reactionmixture was concentrated under a stream of nitrogen to give the titledcompound (200 mg), as a mixture of mono- and bis-sulphonated product.

Experimental MH⁺ 567.1; expected 567.0

Similarly prepared from Preparation 51 (except for Preparation 4, whichwas prepared from Preparation 23) were:

MS (ES): M/Z [MH+] Prep R1a R3 (expected mass) 2 CF₃methylsulfonylmethyl 547.0 (547.0) 3 SF₅ Me 527.0 (527.0) 4 CF₃ benzyl547.1 (545.1) 5 ′ 2-phenylethenyl 555.2 (555.0)

Preparation 6N-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)-N-(cyclopropylmethyl)methanesulfonamide

To a solution of Preparation 15 (100 mg, 0.21 mmol) in acetone (4 ml)was added iv potassium carbonate (38 mg, 0.28 mmol), followed bybromocyclopropane (25 μl, 0.26 mmol). The reaction mixture was thenheated at reflux for 2 h. The reaction mixture was concentrated undernitrogen and the residue partitioned between ethyl acetate and water.The two layers were separated and the aqueous layer was extracted withethyl acetate (×2). The combined organic phases were dried (MgSO₄) andconcentrated under nitrogen to give the titled compound (100 mg).

Experimental MH⁺ 523.4; expected 523.1

Similarly prepared were:

MS (ES): M/Z From [MH+] Prep (expected Prep R1a R4 R3 no. mass) 7 CF₃cyanomethyl Me 15 508.3; (508.0) 8 ′ pyridin-2- Me ′ 560.4; (560.1)ylmethyl 9 Benzyl Me ′ 559.4; (559.1) 10 ′ 2-hydroxyethyl Me ′ 515.0;(513.1) 11 ′ methylthiomethyl Me ′ 531.0; (529.0) 12 ′ cyclcobutyltrifluoromethyl 16 577.0; (577.1) 13 ′ 2-N,N- Me 15 540.0; (540.1)dimethylamino- ethyl 14 SF₅ Me trifluoromethyl 45 594.9; (595.0)

Preparation 15N-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)methanesulfonamide

To Preparation 19 (3.4 g, 6.21 mmol) in a mixture of tetrahydrofuran (35ml) and methanol (35 ml) was added potassium carbonate (2.15 g, 15.53mmol). The reaction mixture was then stirred at room temperature for 2h.

The reaction mixture was concentrated in vacuo and to the residue wasadded ethyl acetate. The solution was washed with hydrochloric acid (1N)and brine and then concentrated in vacuo. The residue was purified bycolumn chromatography (silica, 50 g) with gradient elution,dichloromethane:methanol [100:0 to 95:5]. The appropriate fractions werecombined and concentrated to give the titled compound (620 mg).

¹H-NMR (DMSO): 2.67-2.70 (3H), 2.90-2.95 (3H), 2.99-3.02 (3H), 8.19-8.23(2H), 8.30-8.33 (1H), 9.43-9.47 (1H)

Preparation 16N-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)-1,1,1-trifluoromethanesulfonamide

To a solution of Preparation 46 (650 mg, 0.99 mmol) in trifluoroethanol(9 ml) was added aqueous sodium hydroxide solution (2.5N, 16 drops). Thereaction mixture was then stirred at room temperature, under nitrogen,for 1 h. To the reaction mixture was added hydrochloric acid (2M, 2 ml)and the solution was concentrated in vacuo. The residue was partitionedbetween ethyl acetate (20 ml) and water (20 ml) and the two phases wereseparated. The organic phase was washed with water (2×20 ml), dried(Na₂SO₄) and concentrated in vacuo to give the titled compound (505 mg).

Experimental MW 523.2; expected 523.0

Preparation 17N-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)-N-(methylsulfonyl)cyclopropanesulfonamide

To a solution of Preparation 15 (150 mg, 0.32) and triethylamine (66 μl,0.48 mmol) in dichloromethane (3 ml) was added cyclopropanesulphonylchloride (35 mg, 0.48 mmol). The reaction mixture was then stirred atroom temperature overnight. The reaction mixture was concentrated invacuo and the residue was purified using an Isolute™ cartridge (silica,10 g) with gradient elution, cyclohexane:ethyl acetate [3:1 to 1:1]. Theappropriate fractions were combined and concentrated to give the titledcompound (150 mg).

Experimental MW 572.9; expected 573.0

Similarly prepared were:

From MS (ES): M/Z [MH+] Prep R1a R2 R4 prep (expected mass) 18 CF₃ CNN,N- 15 575.9; (576.0   dimethylamino sulfonyl 19 ′ ′ methylsulfonyl 51547.4; (547.1) 20 SF₅ CF₃ ′ 71 647.9; (648.0) 21 OCF₃ CN ′ 72 578.9;(579.0) 22 OCHF₂ ′ ′ 73 544.9; (545.0)

Preparation 23N′-{4-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-5-yl}-N,N-dimethylimidoformamide

To a solution of Preparation 53 (9.0 g, 15.15 mmol) in tetrahydrofuran(120 ml) was added tetrabutylammonium fluoride (60.6 ml, 60.6 mmol) over5 min. The reaction mixture was heated at 50° C. for 1 h and thenallowed to cool to room temperature. The reaction mixture wasconcentrated in vacuo and the residue was partitioned between ethylacetate (200 ml) and water (200 ml). The organic layer was separated,washed with water (2×200 ml) and brine (200 ml), dried (MgSO₄) andconcentrated in vacuo. The residue was purified by column chromatography(silica, 250 g) with gradient elution, ethyl acetate:dichloromethane[0:1 to 1:4]. The appropriate fractions were combined and concentratedto give the titled compound (2.6 g).

Experimental MH⁺ 449.0; expected 449.0

Alternative Synthesis

A solution of Preparation 55 (10.0 g, 21.0 mmol) in methanol (300 ml)was placed under a hydrogen atmosphere (50 psi), with platinum (5% oncharcoal, 1 g), at room temperature for 2 h. The reaction mixture wasfiltered and concentrated in vacuo and the residue was triturated withdiethyl ether. The solution was concentrated in vacuo to give the titledcompound (8.5 g).

¹H-NMR (CDCl3): 2.74-2.78 (3H), 2.96-2.99 (3H), 7.76-7.81 (2H),8.18-8.21 (1H)

Preparation 24N-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)-N-(2,2,2-trifluoroethyl)methanesulfonamide

To a solution of Preparation 3 (239 mg, 0.45 mmol) in1-methyl-2-pyrrolidinone (4 ml) was added sodium hydride (60% in oil, 12mg, 0.50 mmol). The mixture was stirred at room temperature for 5 minand 2,2,2-trifluoroethyltrichloromethane sulphonate (166 mg, 0.59 mmol)was added. The reaction mixture was then stirred overnight at roomtemperature. To the reaction mixture was added brine (10 ml) and themixture was adjusted to pH 4 by addition of hydrochloric acid (2N). Themixture was extracted with ethyl acetate (2×10 ml) and the combinedextracts were dried (MgSO₄) and concentrated in vacuo. The residue waspurified by column chromatography (silica) eluting with ethylacetate/hexane [1:3]. The appropriate fractions were combined andconcentrated to give the titled compound (82 mg).

Experimental MH⁺ 609.0; expected 609.0

Preparation 25N-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)-N-{[1-(trifluoromethyl)cyclopropyl]methyl}methanesulfonamide

To a solution of Preparation 3 (147 mg, 0.28 mmol) in acetonitrile (6ml) was added Preparation 52 (107 mg, 0.36 mmol) in acetonitrile (2 ml),followed by caesium carbonate (91 mg, 0.59 mmol) and potassium iodide(catalytic amount). The reaction mixture was then heated at reflux for 5h. The reaction mixture was concentrated in vacuo and the residue waspartitioned between water (10 ml) and ethyl acetate (15 ml). The twolayers were separated and the aqueous layer was adjusted to pH 1 byaddition of hydrochloric acid (2N) and re-extracted with ethyl acetate(10 ml). The combined organic phases were dried (MgSO₄) and concentratedin vacuo. The residue was purified by column chromatography (silica)with gradient elution, ethyl acetate:hexane [1:4 to 1:2]. Theappropriate fractions were combined and concentrated to give the titledcompound (155 mg).

Experimental MH⁺ 649.0; expected 649.0

Preparation 263-cyclopropyl-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazole-4,5-diamine

To a solution of Preparation 56 (150 mg, 0.30 mmol) in ethanol (5 ml)was added tin(II) chloride (288 mg, 1.52 mmol). The reaction mixture washeated at reflux for 6 h, cooled and hydrochloric acid (6N, 0.5 ml) wasadded. The reaction mixture was then heated at reflux for a further 16h. To the reaction mixture was added ethyl acetate (25 ml), water andsaturated aqueous sodium hydrogencarbonate solution. The two layers wereseparated and the organic layer was dried (MgSO₄) and concentrated invacuo to give the titled compound as a mixture of products.

Experimental MH⁺ 409.0; expected 409.01

Similarly prepared were:

From prep MS (ES): M/Z [MH+] Prep R1b R2 no. (expected mass) 27 Cl H 57369.0; (369.0) 28 H CN 58 360.0; (360.0)

Preparation 294-amino-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-methoxy-1H-pyrazole-3-carbonitrile

To a solution of Preparation 59 (530 mg, 1.21 mmol) in ethanol (10 ml)was added tin(II) chloride (1.14 g, 6.05 mmol), followed by hydrochloricacid (6N, 1 ml). The reaction mixture was then heated at reflux for 2 h.The reaction mixture was concentrated in vacuo and to the residue wasadded ethyl acetate (40 ml). The solution was then washed with water (30ml) and brine (30 ml), dried (MgSO₄) and concentrated in vacuo to givethe titled compound (495 mg).

Experimental MH⁺ 408.9; expected 409.0

Preparation 304-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-(methylamino)-1H-pyrazole-3-carbonitrile

To a solution of Preparation 65 (40 mg, 0.11 mmol) in ethanol (2.5 ml)was added iron powder (57 mg, 1.0 mmol), calcium chloride (13 mg, 0.11mmol) and water (0.5 ml). The reaction mixture was heated at reflux for6 h and then stirred at room temperature for 8 h. The reaction mixturewas filtered through Celite®, washing through with ethyl acetate, andthe filtrate was concentrated in vacuo. To the residue was added ethylacetate and the solution was washed with saturated aqueous sodiumhydrogencarbonate solution (10 ml) and brine (10 ml), dried (MgSO₄) andconcentrated in vacuo to give the titled compound (35 mg).

Experimental MH⁺ 349.9; expected 350.0

Similarly prepared were:

From MS (ES): M/Z [MH+] Prep R3a R4a prep (expected mass) 31 H2-morpholin-4-ylethyl 66 507.0; (507.1) 32 H 2-N,N-dimethylaminoethyl 67465.1; (465.1) 33 Me 2-N,N-dimethylaminoethyl 70 479.0; (479.1) 34 H2-pyrrolidin-1-ylethyl 68 491.0; (491.1) 35 H Pyridin-4-ylmehtyl 60485.0; (485)   36 H 2-piperidin-1-ylethyl 69 505.0; (505.1)

Preparation 374-[bis(methylsulfonyl)amino]-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazole-3-carboxamide

Hydrogen chloride was bubbled through methanol (8 ml) for 10 min. To thesolution was added Example 67 (441 mg, 0.73 mmol) and the flow ofhydrogen chloride was maintained for a further 5 min. The reactionmixture was then sealed and left overnight. The reaction mixture wasconcentrated in vacuo and to the residue was added methanol (20 ml) andhydrochloric acid (2N, 10 ml). The mixture was stirred for 1 h and water(30 ml) was added. The mixture was extracted with ethyl acetate (3×20ml) and the combined extracts were dried (MgSO₄) and concentrated invacuo to give the titled compound (450 mg) as a 20:1 mixture of theamide and the methyl ester. Experimental MH⁺ 623.0; expected 623.0

Preparation 38N-(3-acetyl-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)-N-(methylsulfonyl)methanesulfonamide

To a solution of Example 67 (500 mg, 0.83 mmol) in tetrahydrofuran (10ml), at 0° C., was added dropwise methylmagnesium bromide (3M in diethylether, 0.8 ml, 2.48 mmol). The reaction mixture was then stirred at roomtemperature for 2 days. The reaction mixture was poured onto ice, waterand hydrochloric acid (2N). The mixture was stirred for 30 min and thenextracted with ethyl acetate (3×30 ml). The combined extracts were dried(MgSO₄) and concentrated in vacuo. The residue was dissolved inacetonitrile (2 ml) and the solution was purified by automatedpreparative liquid chromatography (Gilson system, 150×30 mm, LUNA II C1810 μm column) using an acetonitrile:water gradient [50:50 to 95:5]. Theappropriate fractions were concentrated to give the titled compound (97mg).

Experimental MH⁺ 622.0; expected 622.0

Preparation 39N-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}methanesulfonamide

To a solution of Example 35 (120 mg, 0.24 mmol) in tetrahydrofuran (5ml) was added aqueous sodium hydroxide solution (1M, 4.25 ml) and thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was acidified by addition of hydrochloric acid (1M) and thenextracted with dichloromethane. The combined extracts were dried(Na₂SO₄) and concentrated in vacuo to give the titled compound (100 mg).

Experimental MH⁺ 429.9; expected 430.0

Similarly prepared were:

MS (ES): M/Z From [MH+] Prep R5a prep (expected mass) 40(2-(dimethylamino)ethyl)(methyl)amino 111 557.0; (557.0) 41(2-piperidin-1-ylethyl)amino Ex 71 583.0; 583.1

Preparation 42N-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)-N-[2-(1H-1,2,4-triazol-1-yl)ethyl]methanesulfonamide

To a mixture of Preparation 74 (154 mg, 0.24 mmol) and 1,2,4-triazole(42 mg, 0.61 mmol) in acetonitrile (10 ml) was added potassium carbonate(40 mg, 0.29 mmol). The reaction mixture was then heated at 60° C.overnight. The reaction mixture was concentrated in vacuo and theresidue was partitioned between dichloromethane (10 ml) and water (10ml). The organic phase was separated, dried (MgSO₄) and concentrated invacuo to give the titled compound (155 mg). Experimental MH⁺ 622.0;expected 622.0

Preparation 434,5-diamino-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazole-3-carbonitrile

To a solution of Preparation 23 (300 mg, 0.67 mmol) in methanol (8 ml)and dioxane (1 ml) was added hydrochloric acid (2M, 8 ml). The reactionmixture was then heated at reflux overnight. The reaction mixture wasconcentrated in vacuo and the residue was partitioned between ethylacetate and water. The organic layer was separated, dried (MgSO₄) andconcentrated in vacuo to give the titled compound (273 mg).

Experimental MH⁺ 394.0; expected 394.0

Preparation 44N-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[phenylmethylene]amino}-1H-pyrazol-4-yl)-N-(methylsulfonyl)methanesulfonamide

To a solution of Example 26 (100 mg, 0.18 mmol) in toluene (5 ml) wasadded benzaldehyde (0.04 ml, 0.36 mmol), p-toluenesulphonic acid(catalytic amount) and some 4A molecular sieves. The reaction mixturewas heated at 90° C. for 8 h and then stirred at room temperature for 15h. The reaction mixture was concentrated in vacuo and the residue waspartitioned between ethyl acetate (10 ml) and water (10 ml). The twolayers were separated and the aqueous layer was extracted with ethylacetate (2×10 ml). The combined organic phases were washed with brine,dried (MgSO₄) and concentrated in vacuo to give the titled compound (120mg).

Experimental MH⁺ 637.9; expected 638.0

Preparation 45N-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)-1,1,1-trifluoromethanesulfonamide

To a solution of Preparation 23 (200 mg, 0.45 mmol) in anhydrousdichloromethane (5 ml), at 0° C., was added triethylamine (124 μl, 0.89mmol) and trifluoromethanesulphonic anhydride (150 μl, 0.89 mol). Thereaction mixture was then stirred under nitrogen for 30 min. To thereaction mixture was added dichloromethane and hydrochloric acid (4M, 3ml). The organic phase was separated, washed with hydrochloric acid (4M)and brine, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by column chromatography (silica, 25 g) with gradient elution,ethyl acetate:cyclohexane [2:1 to 1:0], followed by methanol. Theappropriate fractions were combined and concentrated to give the titledcompound (200 mg).

Experimental MH⁺ 580.9; expected 581.0

Similarly prepared was:

Preparation 46N-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[dimethylamino)methylene]amino}-1H-pyrazol-4-yl)-N,

N-bis-(1,1,1-trifluoromethane)sulphonamide, from Preparation 51 (800 mg,2.05 mmol) and trifluoromethanesulphonic anhydride (860 μl, 2.05 mol) togive the title compound (1.3

Experimental MH⁺ 655.3; expected 655.0

Preparation 47N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-iodo-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide

To a mixture of Example 32 (447 mg, 0.81 mmol) and iodine (881 mg, 3.47mmol) in acetonitrile (10 ml) was added isoamylnitrite (0.13 ml, 0.97mmol). The reaction mixture was then heated at 50° C. for 1 h. To thereaction mixture was added saturated aqueous sodium thiosulphatesolution (30 ml) and the mixture was extracted with ethyl acetate (2×20ml). The combined extracts were washed with brine (50 ml), dried (MgSO₄)and concentrated in vacuo. The residue was dissolved in acetonitrile (2ml) and purified by automated preparative liquid chromatography (Gilsonsystem, 150 mm×50 mm

Phenomonex LUNA C18(2) 10 μm column) using an acetonitrile:watergradient [55:45 to 95:5]. The appropriate fractions were concentrated invacuo to give the titled compound (283 mg).

¹H-NMR (CDCl3): 3.24-3.28 (3H), 4.07-4.20 (1H), 4.35-4.49 (1H),7.90-7.93 (2H)

Preparation 48N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-[(2-oxoethyl)amino]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide

To a solution of Preparation 75 (560 mg, 0.94 mmol) in aqueous acetone(10%, 16.6 ml) was added osmium tetroxide solution (2.5%, 33 μmol). Tothe mixture was added sodium periodate (880 mg, 2.07 mmol) and thereaction mixture was stirred at room temperature overnight. The reactionmixture was filtered and the filtrate was concentrated in vacuo. Theresidue was partitioned between dichloromethane and water and theorganic layer was separated, dried (MgSO₄) and concentrated in vacuo togive the titled compound (134 mg).

¹H-NMR (CDCl3): 3.17-3.20 (3H), 4.20-4.29 (2H), 4.32-4.46 (2H),4.76-4.81 (1H), 7.91-7.93 (2H), 9.58-9.59 (1H)

Preparation 49N-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)-1,1,1-trifluoro-N-methylmethanesulfonamide

To a solution of Preparation 46 (1.3 g, 1.98 mmol) in tetrahydrofuran(11 ml), at 0° C., was added potassium carbonate (685 mg, 4.96 mmol) inmethanol (11 ml) and water (3 drops). The reaction mixture was thenstirred at room temperature for 2 h. The reaction mixture wasconcentrated in vacuo and to the residue was added dichloromethane. Thesolution was washed with hydrochloric acid (1N) and brine, dried (MgSO₄)and concentrated in vacuo. The residue was purified by columnchromatography (silica, 50 g) with gradient elution,cyclohexane:dichloromethane [1:0 to 0:1], followed bydichloromethane:methanol [95:5]. The appropriate fractions were combinedand concentrated to give the titled compound (240 mg).

¹H-NMR (CDCl3): 2.79-2.85 (3H), 3.02-3.08 (3H), 3.45-3.51 (3H),7.69-7.74 (2H), 8.02-8.07 (1H)

Preparation 50N′-[3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(1,1-dioxidoisothiazolidin-2-yl)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide

A mixture of Preparation 76 (127 mg, 0.24 mmol) and potassium carbonate(36 mg, 0.26 mmol) in N,N-dimethylformamide (2 ml) was stirred at roomtemperature for 2 h. To the reaction mixture was added ethyl acetate (10ml) and water (10 ml) and the two layers were separated. The aqueouslayer was extracted with ethyl acetate (×2) and the combined organicphases were dried (MgSO₄) and concentrated in vacuo to give the titledcompound (110 mg).

Experimental MH⁺ 495.2; expected 495.0

Preparation 51N′-{4-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}-N,N-dimethylimidoformamide

To a solution of Preparation 77 (423 mg, 0.79 mmol) in tetrahydrofuran(15 ml) was added tetrabutylammonium fluoride (1M in tetrahydrofuran,3.2 ml, 3.2 mmol). The reaction mixture was then heated at 50° C. for 1h. The reaction mixture was concentrated in vacuo and the residuepartitioned between dichloromethane (20 ml) and water (20 ml). Theorganic phase was separated, dried (MgSO₄) and concentrated in vacuo.The residue was purified by column chromatography with gradient elution,ethyl acetate:hexane [1:2 to 4:1]. The appropriate fractions werecombined and concentrated to give the titled compound (220 mg, 71%).

Experimental MH⁺] 391.2; expected 391.1

Alternative Synthesis

A solution of Preparation 61 (1.20 g, 2.85 mmol) in methanol (25 ml) wasplaced under a hydrogen atmosphere (15 psi), with platinum (5% oncharcoal), at room temperature for 3 h. The reaction mixture wasfiltered through a pad of Arbocel®, washing through withdichloromethane/methanol and the filtrate was concentrated in vacuo. Theresidue was purified using an Isolute™ cartridge (silica, 25 g), elutingwith dichloromethane/methanol [99:1]. The appropriate fractions werecombined and concentrated to give the titled compound (1.0 g).

Experimental MH⁺ 391.1; expected 391.1

Preparation 52 [1-(trifluoromethyl)cyclopropyl]methyl4-methylbenzenesulfonate

To a solution of 1-(trifluoromethyl)cyclopropyl]methanol (J. FluorineChem., 2001, 109, 2, 95, 8.18 g, 58.4 mmol) in dichloromethane (50 ml),at 0° C., was added triethylamine (50 ml), 4-dimethylaminopyridine (713mg, 5.84 mmol) and p-toluenesulphonyl chloride (11.1 g, 58.4 mmol). Thereaction mixture was allowed to warm to room temperature and stirredovernight. The reaction mixture was concentrated in vacuo and theresidue was partitioned between diethyl ether (250 ml) and hydrochloricacid (0.5M, 100 ml). The two layers were separated and the aqueous phasewas extracted with diethyl ether (100 ml). The combined organic phaseswere washed with saturated aqueous sodium hydrogencarbonate solution (50ml) and brine (50 ml), dried (MgSO₄) and concentrated in vacuo. Theresidue was purified using a Biotage™ Flash 40 system with gradientelution, diethyl ether:cyclohexane [5:95 to 20:80]. The appropriatefractions were combined and concentrated to give the titled compound(11.8 g).

¹H-NMR (CDCl3): 0.81-0.89 (2H), 1.09-1.16 (2H), 2.44-2.48 (3H),4.09-4.12 (2H), 7.33-7.39 (2H), 7.77-7.82 (2H)

Preparation 53 2-(trimethylsilyl)ethyl3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-ylcarbamate

To a solution of Preparation 78 (6.7 g, 14.0 mmol), triethylamine (2.14ml, 15.4 mmol) and 2-trimethylsilylethanol (2.21 ml, 15.4 mmol) in1,4-dioxane (100 ml) was added diphenylphosphoryl azide (3.34 ml, 15.4mmol). The reaction mixture was heated at reflux for 3 h and thenstirred overnight at room temperature. To the reaction mixture was addedethyl acetate (200 ml) and the mixture was washed with hydrochloric acid(1M, 2×250 ml). The aqueous phase was re-extracted with ethyl acetate(200 ml) and the organic phases were combined, washed with brine (200ml), dried (Na₂SO₄) and concentrated in vacuo. The residue was purifiedby column chromatography (silica, 300 g) with gradient elution,methanol:dichloromethane [0:100 to 5:95]. The appropriate fractions werecombined and concentrated to give the titled compound (9.0 g).

Experimental MH⁺ 593.0; expected 593.1

Similarly prepared was:

Preparation 54 2-(trimethylsilyl)ethyl1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(dimethylamino)methylene]amino}-3-(trifluoromethyl)-1H-pyrazol-4-ylcarbamate

from the compound of Preparation 80 (1.22 g, 2.35 mmol),diphenylphosphoryl azide (0.56 ml, 2.59 mmol) and 2-silylethanol (0.37ml, 2.59 mmol) to give the title compound (0.91 g).

Experimental MH⁺ 636.0; expected 636.1

Preparation 55N-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-nitro-1H-pyrazol-5-yl}-N,N-dimethylimidoformamide

To a solution of nitronium tetrafluoroborate (470 mg, 3.5 mmol) inacetonitrile (15 ml) was added Preparation 81 (1.0 g, 2.9 mmol). Thereaction mixture was then stirred at room temperature for 2 h. Thereaction mixture was diluted with ethyl acetate, washed with water andsaturated brine solution, dried (MgSO₄) and concentrated in vacuo togive the titled compound (960 mg).

Experimental MH⁺ 478.8; expected 479.0

Similarly prepared were:

MS (ES): M/Z From [MH+] prep R1a R1b R2a R3a prep (expected mass) 56 SF₅Cl cyclopropyl

82 494.0; (494.0) 57 ″ ′ H ″ 83 454.0; (454.0) 58 ″ H CN ″ 84 59 ″ Cl ″OMe 93 * 60 ′ ′ pyridin-4- 94 514.9; (515.0) ylmethyl)amino 61 CF₃ ′ ″

85 ** 62 OCF₃ ′ ″ ″ 87 437.0; (437.0) 63 SCF₃ ′ ″ ″ 88 453.0; (453.0) 64OCHF₂ ′ ″ ″ 89 419.0; (419.0) *¹H-NMR (CDCl3): 4.24-4.33 (3H), 7.89-7.96(2H) **¹H-NMR (DMSO): 2.73-2.77 (3H), 3.06-3.09 (3H), 8.20-8.27 (2H),8.53-8.56 (1H)

Preparation 651-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-(methylamino)-4-nitro-1H-pyrazole-3-carbonitrile

A mixture of5-bromo-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-nitro-1H-pyrazole-3-carbonitrile(EP 295118 A1, 50 mg, 0.12 mmol) and methylamine (2M in tetrahydrofuran,1.0 mmol, 2.0 mmol) was heated at 55° C. for 2.5 h. To the reactionmixture was added water (5 ml), followed by ethyl acetate (5 ml). Thetwo layers were separated and the aqueous layer was extracted with ethylacetate (3×5 ml). The combined organic phases were dried (MgSO₄) andconcentrated in vacuo to give the titled compound (42 mg).

¹H-NMR (CDCl3): 2.65-2.69 (3H), 7.29-7.37 (1H), 7.76-7.80 (2H)

Similarly prepared from Preparation 92 were:

MS (ES): M/Z [MH+] Prep R12 R13 (expected mass) 66 H2-morpholin-4-ylethyl 537.0; (537.0) 67 H 2-(dimethylamino)ethyl 495.0;(495.0) 68 H 2-pyrrolidin-1-ylethyl 521.1; (521.0) 69 H2-piperidin-1-ylethyl 535.0; (535.0) 70 Me 2-(dimethylamino)ethyl 509.0;(509.0)

Preparation 71N′-[4-amino-1-[2,6-dichloro-4-pentafluorothiophenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide

To a solution of Preparation 54 (0.91 g, 1.43 mmol) in tetrahydrofuran(27 ml) was added tetrabutylammonium fluoride (5.7 ml, 5.7 mmol), viasyringe. The reaction mixture was then heated at 50° C. for 1 h. Thereaction mixture was concentrated in vacuo and the residue waspartitioned between dichloromethane and water. The organic phase wasthen separated, dried (MgSO₄) and concentrated in vacuo. The residue waspurified by column chromatography with gradient elution, ethylacetate:cyclohexane [1:4 to 2:3]. The appropriate fractions werecombined and concentrated to give the titled compound (0.64 g).

Experimental MH⁺ 491.9; expected 492.0

Preparation 72N′-{4-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethoxy)phenyl]-1H-pyrazol-5-yl}-N,N-dimethylimidoformamide

To a solution of Preparation 62 (750 mg, 1.91 mmol) in methanol wasadded platinum (10 wt. % on carbon) and the mixture was placed in ahydrogen atmosphere (50 psi) for 8 h. The reaction mixture was filteredthrough Arbocel® and the filtrate was concentrated in vacuo. The residuewas partitioned between dichloromethane and water and the organic phasewas separated, dried and concentrated in vacuo to give the titledcompound (650 mg).

Experimental MH⁺ 407.0; expected 407.0

Preparation 73N′-{4-amino-3-cyano-1-[2,6-dichloro-4-(difluoromethoxy)phenyl]-1H-pyrazol-5-yl}-N,N-dimethylimidoformamide

from the compound of Preparation 64 (850 mg, 2.03 mmol) to give thetitle compound (580 mg).

Experimental MH⁺ 389.0; expected 389.0

Preparation 74N-(2-bromoethyl)-N-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)methanesulfonamide

To a mixture of Preparation 3 (166 mg, 0.32 mmol) and 1,2-dibromoethane(0.14 ml, 1.58 mmol) in acetonitrile (12 ml) was added potassiumcarbonate (52 mg, 0.38 mmol). The reaction mixture was then heated at70° C. overnight. The reaction mixture was concentrated in vacuo and theresidue was partitioned between dichloromethane (30 ml) and water (30ml). The organic phase was separated, dried (MgSO₄) and concentrated invacuo to give the titled compound (154 mg).

Experimental MH⁺ 632.9; expected 632.9

Preparation 75N-{5-(allylamino)-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide

To a solution of Example 32 (3.0 g, 5.4 mmol) in tetrahydrofuran (27ml), at 0° C., was added sodium hydride (0.24 g, 5.94 mmol). The mixturewas allowed to warm to room temperature and allyl bromide (2.3 ml, 27.0mmol) was added. The reaction mixture was then stirred at roomtemperature for 2 days. To the reaction mixture was added water andethyl acetate. The organic layer was separated, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by column chromatographywith gradient elution, ethyl acetate:cyclohexane [5:95 to 1:5]. Theappropriate fractions were combined and concentrated to give the titledcompound (1.34 g).

Experimental MH⁺ 594.1; expected 594.0

Preparation 763-chloro-N-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)propane-1-sulfonamide

To a solution of Preparation 51 (100 mg, 0.26 mmol) in pyridine (2 ml),under nitrogen, was added 3-chloropropanesulphonyl chloride (34 μl, 0.28mmol) and the reaction mixture was stirred overnight at roomtemperature. To the reaction mixture was added ethyl acetate (10 ml) andwater (10 ml) and the two layers were separated. The aqueous layer wasextracted with ethyl acetate (×2) and the combined organic phases werewashed with hydrochloric acid (1M), water and brine, dried (MgSO₄) andconcentrated in vacuo to give the titled compound (127 mg).

Experimental MH⁺ 529.1; expected 529.0

Preparation 77 2-(trimethylsilyl)ethyl3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-ylcarbamate

To a solution of Preparation 79 (420 mg, 1.0 mmol) in 1,4-dioxane (6 ml)was added triethylamine (0.15 ml, 1.1 mmol) and2-(trimethylsilyl)ethanol (0.16 ml, 1.1 mmol), followed by the dropwiseaddition of diphenylphosphoryl azide (0.24 ml, 1.1 mmol). The reactionmixture was then heated at reflux overnight. The reaction mixture wasconcentrated in vacuo and the residue partitioned between ethyl acetate(20 ml) and hydrochloric acid (1N, 20 ml). The organic phase wasseparated, dried (MgSO₄) and concentrated in vacuo. The residue waspurified by column chromatography with gradient elution, ethylacetate:hexane [1:2 to 2:1]. The appropriate fractions were combined andconcentrated to give the titled compound (423 mg). Experimental MW535.4; expected 535.1

Preparation 783-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazole-4-carboxylicacid

To a solution of Preparation 95 (8.0 g, 16.25 mmol) in anhydrouspyridine (80 ml) was added lithium iodide (10.9 g, 81.25 mmol). Thereaction mixture was then heated at reflux, under nitrogen, overnight.The reaction mixture was concentrated in vacuo and the residue waspartitioned between ethyl acetate (200 ml) and hydrochloric acid (2N,200 ml). The organic layer was separated, washed with hydrochloric acid(2N, 2×200 ml) and brine (200 ml), dried (Na₂SO₄) and concentrated invacuo. The residue was purified by column chromatography (silica, 300 g)with gradient elution, methanol:dichloromethane [0.5:95.5 to 10:90]. Theappropriate fractions were combined and concentrated to give the titledcompound (6.7 g).

Experimental MH⁺ 477.8; expected 478.0

Similarly prepared were:

Preparation 793-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazole-4-carboxylicacid

from the compound of Preparation 90 (2.0 g, 4.61 mmol) to give thetitled compound (1.5 g).

Experimental MH⁺ 420.2; expected 420.0

Preparation 801-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(dimethylamino)methylene]amino}-3-(trifluoromethyl)-1H-pyrazole-4-carboxylicacid

from the compound of Preparation 91 (2.12 g, 4.1 mmol) to give thetitled compound (1.22 g).

Experimental MH⁺ 521.0; expected 521.0

Preparation 81N′-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-5-yl}-N,N-dimethylimidoformamide

To a solution of Preparation 86 (2.2 g, 3.9 mmol) in dry tetrahydrofuran(30 ml), at −30° C., was added isopropylmagnesium chloride (2M inN,N-dimethylformamide, 2.2 ml, 4.4 mmol). The reaction mixture was thenallowed to warm to room temperature over 1 h. To the reaction mixturewas added saturated aqueous ammonium chloride solution (10 ml) and ethylacetate (excess). The organic layer was separated, washed with saturatedbrine solution, dried (MgSO₄) and concentrated in vacuo to give thetitled compound (1.6 g).

Experimental MH⁺ 433.8; expected 434.0

Preparation 82N′-{3-cyclopropyl-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-5-yl}-N,N-dimethylimidoformamide

A solution of Preparation 96 (3.3 g, 8.40 mmol) in N,N-dimethylformamidedimethyl acetal (15 ml) was heated at reflux for 2 h. The reactionmixture was concentrated in vacuo and the residue was absorbed ontosilica and purified by column chromatography, eluting withcyclohexane/ethyl acetate [4:1]. The appropriate fractions were combinedand concentrated to give the titled compound (3.7 g). Experimental MH⁺449.0; expected 449.0

Similarly prepared were:

From MS (ES): M/Z [MH+] Prep R1a R1b R2a R3a prep (expected mass) 83 SF₅Cl H H  97 409.0; (409.01) 84 ″ H CN ″  99 400.0; (400.0) 85 CF₃ Cl ″″ * *** 86 SF₅ ″ ″ I ** **** 87 OCF₃ ″ ″ H 104 392.0; is (392.0) 88 SCF₃″ ″ ″ 103 408.0; (408.0) 89 OCHF₂ ″ ″ ″ 106 374.0; (374.0) 90 CF₃ ″ ″—CO₂Me 107 434.2; (434.1) 91 SF₅ ″ CF₃ ″ 108 535.0; (535.0)*5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonitrile(WO 9839302 A1)**5-amino-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-iodo-1H-pyrazole-3-carbonitrile(WO 9824761 A1, WO 9804530 A1) ***¹H-NMR (DMSO): 2.63-2.65 (3H),2.96-2.98 (3H), 6.61-6.63 (1H), 8.13-8.15 (1H), 8.16-8.18 (2H)****¹H-NMR (CDCl3): 2.77-2.81 (3H), 3.02-3.05 (3H), 7.78-7.81 (2H),8.21-8.24 (1H)

Preparation 925-bromo-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-nitro-1H-pyrazole-3-carbonitrile

To a solution of Preparation 98 (5.0 g, 12.0 mmol) and bromoform (16 ml,18.3 mmol) in acetonitrile (50 ml) was added dropwise tent-butyl nitrite(8 ml, 67.3 mmol). The reaction mixture was then heated at 55° C. for 16h. The reaction mixture was concentrated in vacuo and the residue wasre-crystallised from cyclohexane/ethyl acetate [20:1] to give the titledcompound (3.1 g).

¹H-NMR (CDCl3): 7.92-7.97 (2H)

Preparation 931-[2,6-dichloro-4-pentafluorothiophenyl]-5-methoxy-1H-pyrazole-3-carbonitrile

To a solution of Preparation 100 (650 mg, 1.71 mmol) in acetonitrile (15ml) was added potassium carbonate (708 mg, 5.13 mmol) and methyl iodide(0.32 ml, 5.14 mmol) and the reaction mixture was heated at 40° C.overnight. The reaction mixture was concentrated in vacuo and theresidue was partitioned between water (30 ml) and ethyl acetate (30 ml).The two layers were separated and the organic layer was washed withbrine (30 ml), dried (MgSO₄) and concentrated in vacuo. The residue waspurified by column chromatography with gradient elution, hexane:ethylacetate [5:1 to 3:1]. The appropriate fractions were combined andconcentrated to give the titled compound (474 mg).

Experimental MH⁺ 393.9; expected 394.0

Preparation 941-[2,6-dichloro-4-pentafluorothiophenyl]-5-[(pyridin-4-ylmethyl)amino]-1H-pyrazole-3-carbonitrile

To a mixture of5-amino-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazole-3-carbonitrile(WO 9306089 A1, 1.00 g, 2.63 mmol) and p-toluenesulphonic acid (5 mg) intoluene (20 ml) was added 4-pyridinecarboxaldehyde (0.35 ml, 3.68 mmol).The reaction mixture was then heated at reflux for 1.5 h. The reactionmixture was partitioned between ethyl acetate and water and the organiclayer was separated, washed with water, dried (MgSO₄) and concentratedin vacuo. To a solution of the residue in methanol (48 ml) was addedsodium borohydride (48 mg, 1.26 mmol) and the mixture was stirred atroom temperature for 2 h. The reaction mixture was concentrated in vacuoand the residue was partitioned between ethyl acetate and water. Theorganic layer was separated, dried (MgSO₄) and concentrated in vacuo togive the titled compound (1.26 g).

Experimental MH⁺ 470.0; expected 470.0

Preparation 95 methyl3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazole-4-carboxylate

A mixture of Preparation 86 (50.0 g, 89.3 mmol), triethylamine (24.9 ml,178.6 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).dichloromethane(2.0 g) in methanol (500 ml) was heated at 65° C. under carbon monoxide(150 psi) for 8 h. To the reaction mixture was added water (2 l) and themixture was stirred for 30 min. The precipitate was collected byfiltration and air-dried to give the titled compound (43.3 g).

¹H-NMR (DMSO): 2.67-2.70 (3H), 3.00-3.03 (3H), 3.72-3.77 (3H), 8.36-8.38(1H), 8.41-8.43 (2H)

Preparation 963-cyclopropyl-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-5-amine

To a solution of Preparation 101 (1.55 g, 14.2 mmol) in 2-propanol (30ml) was added Preparation 102 (4.28 g, 14.2 mmol). The reaction mixturewas heated at reflux for 16 h. The mixture was cooled to roomtemperature and concentrated sulphuric acid (0.1 ml) was added, followedby acetic acid (0.6 ml). The reaction mixture was then heated at refluxfor a further 4 h. The reaction mixture was concentrated in vacuo and tothe residue was added water and saturated aqueous sodiumhydrogencarbonate solution (30 ml). The mixture was extracted with ethylacetate and the combined extracts were dried (MgSO₄) and concentrated invacuo. The residue was absorbed onto silica and purified by columnchromatography with gradient elution, cyclohexane:ethyl acetate [4:1 to2:1]. The appropriate fractions were combined and concentrated to givethe titled compound (3.4 g).

Preparation 971-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-5-amine

To a solution of Preparation 102 (4.0 g, 13.2 mmol) andethylenediaminetetraacetic acid disodium salt (catalytic amount) inmethanol (40 ml), heated at reflux, was added 2-chloroacrylonitrile (3.2ml, 39.6 mmol) dropwise. The reaction mixture was heated at refluxovernight, before addition of sulphuric acid (concentrated, 1.2 ml, 21.1mmol). After heating at reflux for a further 6 h, anhydrous sodiumcarbonate (4.2 g, 39.6 mmol) was added and the reaction mixture wasstirred overnight at room temperature. The reaction mixture wasconcentrated in vacuo and to the residue was added water (150 ml). Themixture was stirred for 60 h and the resulting precipitate was collectedby filtration, washed with water and dried to give the titled compound(4.2 g). Experimental MH⁺ 354.0; expected 354.0

Preparation 985-amino-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-nitro-1H-pyrazole-3-carbonitrile

To a solution of Preparation 55 (10.0 g, 20.9 mmol) in dioxane (160 ml)was added methanol (20 ml) and hydrochloric acid (10%, 20 ml). Thereaction mixture was heated at 90° C. for 56 h and additionalhydrochloric acid (concentrated, 2 ml) was added. The reaction mixturewas then heated at 90° C. for a further 15 h. To the reaction mixturewas added aqueous sodium hydrogencarbonate solution (50 ml) and ethylacetate (100 ml). The two layers were separated and the aqueous layerwas extracted with ethyl acetate (2×100 ml). The combined organic phaseswere washed with brine, dried (MgSO₄) and concentrated in vacuo. Theresidue was triturated with dichloromethane to give the titled compound(6.6 g).

Experimental MH⁺ 424.0; expected 424.0

Preparation 995-amino-1-[2-chloro-4-pentafluorothio-phenyl]-1H-pyrazole-3-carbonitrile

To sulphuric acid (concentrated, 1.75 ml) was added carefully sodiumnitrite (432 mg, 6.26 mmol), followed by glacial acetic acid (2.5 ml).The solution was stirred at 10° C. for 1 h, before Preparation 105 (1.44g, 5.69 mmol) in glacial acetic acid (1 ml) was added dropwise. Themixture was heated at 50° C. for 1 h, allowed to cool to roomtemperature, and then added dropwise to ethyl 2,3-dicyanopropanoate(Hainzl, D.; Cole, L. M.; Casida, J. E. Chemical Research in Toxicology(1998), 11(12), 1529-1535, 864 mg, 5.69 mmol) in acetic acid (1 ml) andice water (2 ml). The reaction mixture was then stirred at roomtemperature for 45 min. The reaction mixture was poured into water (200ml) and the mixture was extracted with dichloromethane (100 ml). To theorganic extract was added aqueous ammonium hydroxide solution (880, 25ml) and water (25 ml) and the mixture was stirred at room temperatureovernight. The reaction mixture was partitioned between dichloromethane(100 ml) and water (100 ml) and the organic phase was separated, dried(MgSO₄) and concentrated in vacuo to give the titled compound (700 mg).

Experimental MH⁺ 345.1; expected 345.0

Preparation 1001-[2,6-dichloro-4-pentafluorothiophenyl]-5-hydroxy-1H-pyrazole-3-carbonitrile

Sodium nitrite (1.32 g, 19.1 mmol) was added carefully to sulphuric acid(concentrated, 6.8 ml), whilst cooling the solution to 0° C. Thesolution was heated to 60° C. for 30 min, allowed to cool and thendiluted with acetic acid (12 ml). To the solution was added2,6-dichloro-4-pentafluorothiophenylamine (WO 9421606 A1, 5.0 mg, 17.4mmol) in acetic acid (11 ml) and the reaction mixture was heated at 55°C. for 1 h. To a solution of dimethyl 2-cyanosuccinate (Hall, H. K.,Jr.; Ykman, P., J. Am. Chem. Soc. (1975), 97(4), 800-807, 3.09 g, 18.1mmol) in acetic acid (24 ml) and water (36 ml) was added dropwise thesolution of the diazonium salt, followed by sodium acetate (24.2 g) inwater (42 ml). The reaction mixture was then stirred at room temperaturefor 30 min. The reaction mixture was poured into ice/water (200 ml) andthe mixture was extracted with dichloromethane (4×60 ml). The combinedextracts were then washed with ammonium hydroxide (48 ml), dried andconcentrated in vacuo. To a solution of sodium methoxide (25 wt. %, 11.5ml, 50.1 mmol) in methanol (450 ml) was added dropwise a solution of theresidue in methanol (100 ml). The reaction mixture was then stirred atroom temperature for 2 h. The reaction mixture was concentrated in vacuoand to the residue was added water. This solution was adjusted to pH 1by addition of hydrochloric acid (4N) and the mixture was extracted withdichloromethane (3×100 ml). The combined extracts were dried (MgSO₄) andconcentrated in vacuo. The residue was purified by columnchromatography, eluting with hexane/ethyl acetate [3:1]. The appropriatefractions were combined and concentrated to give the titled compound(4.5 g).

Experimental MH⁺ 379.8; expected 380.0

Preparation 101 3-cyclopropyl-3-oxopropanenitrile

To a solution of cyanoacetic acid (4.25 g, 50.0 mmol) in tetrahydrofuran(80 ml) and dichloromethane (40 ml), at 0° C., was addedisopropylmagnesium chloride (2M in tetrahydrofuran, 50 ml, 100 mmol). Ina separate reaction vessel, 1,1-carbonyldiimidazole (4.05 g, 25.0 mmol)was added to cyclopropylcarboxylic acid (2.15 g, 25.0 mmol) intetrahydrofuran (80 ml), at 0° C. The two mixtures were combined withadditional tetrahydrofuran (60 ml) and the reaction mixture was stirredat room temperature for 60 h. To the reaction mixture was addedhydrochloric acid (2N), at 0° C., and the mixture was stirred for 1 h.The mixture was concentrated in vacuo and to the residue was addedwater. After extracting with diethyl ether (2×100 ml), the combinedextracts were washed with saturated aqueous sodium hydrogencarbonatesolution (60 ml) and water (60 ml), dried (MgSO₄) and concentrated invacuo to give the titled compound (1.5 g).

¹H-NMR (CDCl3): 1.02-1.08 (2H), 1.13-1.18 (2H), 2.03-2.09 (1H),3.57-3.60 (2H)

Preparation 102 [2,6-dichloro-4-pentafluorothiophenyl]hydrazine

To a mixture of sulphuric acid (concentrated, 24 ml) and sodium nitrite(6.0 g, 87.0 mmol) at 10° C., was added2,6-dichloro-4-pentafluorothiophenylamine (WO 9421606 A1, 23.5 g, 82.0mmol) in glacial acetic acid (92 ml) over 20 min. The reaction mixturewas stirred at 25° C. for 20 min and then heated at 60° C. for 1 h. Thereaction mixture was cooled to 5° C. and tin (II) chloride (65.6 g, 0.35mol) in hydrochloric acid (concentrated, 56 ml) was added. Afterstirring for 30 min, the precipitate was collected by filtration andadded to ammonia (400 ml) and ice (100 ml). This mixture was extractedwith diethyl ether (5×200 ml) and the combined extracts were dried(MgSO₄) and concentrated in vacuo to give the titled compound (19.3 g).

¹H-NMR (CDCl3): 3.61-3.82 (2H), 5.75-5.91 (1H), 7.60-7.65 (2H)

Preparation 1035-amino-1-{2,6-dichloro-4-[(trifluoromethyl)thio]phenyl}-1H-pyrazole-3-carbonitrile

Sodium nitrite (224 mg, 3.25 mmol) was added carefully to sulphuric acid(concentrated, 1 ml), ensuring that the temperature did not rise above30° C. After stirring at 15° C. for 1 h, acetic acid (2 ml) was added,followed by Preparation 109 (850 mg, 3.24 mmol) in acetic acid (3 ml).The reaction mixture was then heated at 50° C. for 1 h and cooled toroom temperature. To a solution of ethyl 2,3-dicyanopropanoate (Hainzl,D.; Cole, L. M.; Casida, J. E. Chemical Research in Toxicology (1998),11(12), 1529-1535, 500 mg, 3.29 mmol) in acetic acid (5 ml) was addedice water (5 ml), followed by the solution of the diazonium salt, addeddropwise at 0° C. After complete addition, ammonium hydroxide (6 ml) wasadded and the reaction mixture was stirred overnight at roomtemperature. The reaction mixture was filtered through Arbocel® and thefiltrate was concentrated in vacuo. The residue was partitioned betweendichloromethane and water and the organic phase was separated, dried(Na₂SO₄) and concentrated in vacuo to give the titled compound (1.0 g).Experimental MH⁺ 353.0; expected 353.0

Preparation 1045-amino-1-[2,6-dichloro-4-(trifluoromethoxy)phenyl]-1H-pyrazole-3-carbonitrile

To sulphuric acid (18M, 54 ml) was added sodium nitrite (13.9 g, 201.2mmol) and the solution was stirred at 15° C. for 1 h. To the solutionwas added acetic acid (200 ml), followed by2,6-dichloro-4-(trifluoromethoxy)aniline (45.0 g, 182.9 mmol) in aceticacid (90 ml), ensuring the temperature of the solution did not riseabove 20° C. After addition was complete, the mixture was heated at 50°C. for 1 h, cooled to room temperature and added dropwise to a solutionof ethyl 2,3-dicyanopropanoate (Hainzl, D.; Cole, L. M.; Casida, J. E.Chemical Research in Toxicology (1998), 11(12), 1529-1535, 27.8 g, 182.9mmol) in acetic acid (115 ml) and ice cold water (145 ml). The reactionmixture was then stirred overnight at room temperature. To the reactionmixture was added dichloromethane (500 ml) and the mixture was stirredfor 10 min. The two phases were separated and the organic phase waswashed with water (200 ml) and ammonia (0.88, 400 ml) was addeddropwise, maintaining the temperature of the mixture below 10° C. Thismixture was stirred overnight at room temperature and the organic phasewas separated and concentrated in vacuo. The residue was re-crystallisedfrom toluene/pentane [2:1] to give the titled compound (22.4 g).

Experimental MH⁺ 337.0; expected 337.0

Preparation 105 2-chloro-4-pentafluorothio-phenylamine

To a solution of 4-(pentafluorothio)phenylamine (WO 9421606 A1, 1.29 g,5.89 mmol) in acetonitrile (15 ml) at 45° C. was addedN-chlorosuccinimide (786 mg, 5.89 mmol). The reaction mixture was thenstirred at 45° C. for 3 h. The reaction mixture was concentrated invacuo and the residue was partitioned between dichloromethane (20 ml)and water (20 ml). The organic phase was separated, dried andconcentrated in vacuo to give the titled compound (1.44 g).

Experimental MH⁺ 254.1; expected 254.0

Preparation 1065-amino-1-[2,6-dichloro-4-(difluoromethoxy)phenyl]-1H-pyrazole-3-carbonitrile

To sulphuric acid (concentrated, 21 ml), at 15° C., was added sodiumnitrite (4.8 g, 69.6 mmol). After stirring for 1 h, glacial acetic acid(17.3 ml) was added, followed by Preparation 110 (13.8 g, 60.3 mmol) inacetic acid (33.8 ml), added dropwise, keeping the temperature of themixture below 25° C. The solution was heated at 50° C. for 1 h, cooledand added dropwise to a mixture of ethyl 2,3-dicyanopropanoate (Hainzl,D.; Cole, L. M.; Casida, J. E. Chemical Research in Toxicology (1998),11(12), 1529-1535, 10.6 g, 69.6 mmol), acetic acid (42.8 ml) andice/water (55 ml), at 0° C. The reaction mixture was then stirred atroom temperature overnight. To the reaction mixture was addeddichloromethane (300 ml) and the mixture was stirred. The two layerswere separated and the organic layer was washed with water. To theorganic layer was added ammonium hydroxide (concentrated, 125 ml) andice and the mixture was stirred at 5° C. for 4 h. The organic layer wasagain separated and stirred overnight with activated charcoal. Themixture was filtered through Celite® and the filtrate was concentratedin vacuo. The residue was purified by column chromatography (Biotage,silica, 90 g), eluting with dichloromethane. The appropriate fractionswere combined and concentrated to give Preparation 136 (3.1 g).

Experimental MH⁺ 319.0; expected 319.0

Preparation 107 methyl5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxylate

A mixture of5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-iodo-1H-pyrazole-3-carbonitrile(WO 9828278 A1, 18 g, 40.3 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (600 mg) andtriethylamine (10 ml), in methanol (150 ml), was placed in a pressurevessel and heated at 60° C. under carbon monoxide (100 psi) for 60 h.The reaction mixture was filtered through Celite® and the filtrateconcentrated in vacuo. To the residue was added ethyl acetate and thissolution was washed with hydrochloric acid (0.2M) and brine. The organicphase was then separated, dried and concentrated in vacuo. The residuewas purified by flash column chromatography, eluting with ethylacetate/hexane (1:5). The appropriate fractions were combined andconcentrated and the residue re-crystallised from methanol to give thetitled compound (100 mg).

Experimental MH⁺ 379.0; expected 379.0

Preparation 108 methyl5-amino-1-[2,6-dichloro-4-pentafluorothiophenyl]-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate

To a mixture of Preparation 102 (3.95 g, 13.1 mmol) and potassiumcarbonate (2.16 g, 15.6 mmol) in diethyl ether (15 ml), at 0° C., wasadded dropwise methyl (22)-3-chloro-2-cyano-4,4,4-trifluorobut-2-enoate(WO 8703781 A1, 2.79 g, 13.1 mmol) in diethyl ether (6 ml). The reactionmixture was then stirred at room temperature overnight. The reactionmixture was pre-absorbed onto silica and purified by columnchromatography with gradient elution, hexane:ethyl acetate [4:1 to 2:1].The appropriate fractions were combined and concentrated to give thetitled compound (2.3 g).

¹H-NMR (CDCl3): 3.86-3.88 (3H), 5.30-5.40 (2H), 7.86-7.91 (2H)

Preparation 109 2,6-dichloro-4-[(trifluoromethyl)thio]phenylamine

To a solution of 4-[(trifluoromethyl)thio]phenylamine (EP 546391 A2, 4.8g, 25.0 mmol) in acetonitrile (50 ml), at 50° C., was addedN-chlorosuccinimide (6.7 g, 50.0 mmol). The reaction mixture was thenstirred at 50° C. for 1 h. To the reaction mixture was added water (150ml) and the mixture was extracted with dichloromethane (100 ml). Thecombined extracts were dried (MgSO₄) and concentrated in vacuo to givethe titled compound (1.0 g).

Preparation 110 2,6-dichloro-4-(difluoromethoxy)phenylamine

To a solution of 4-[(difluoromethoxy)methyl]aniline (15.0 g, 94.3 mmol)in acetonitrile (150 ml) was added N-chlorosuccinimide (25.2 g, 18.9mmol) and the reaction mixture was stirred under nitrogen for 2 h. Thereaction mixture was concentrated in vacuo and the residue waspartitioned between diethyl ether (500 ml) and water (125 ml). Theorganic layer was separated, washed with aqueous sodium thiosulphatesolution, water and brine, dried (MgSO₄) and treated with charcoal. Thesolution was then filtered and concentrated in vacuo. The residue wasextracted with hexane (2×300 ml) and the combined extracts wereconcentrated in vacuo to give the titled compound (13.8 g).

Experimental MH⁺ 228.0; expected 228.0

Preparation 111N-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[3-(dimethylamino)propyl]amino}-1H-pyrazol-4-yl)-N-(methylsulfonyl)methanesulfonamide

To a mixture of Preparation 33 (550 mg, 1.0 mmol) and triethylamine(0.33 ml, 2.3 mmol) in dichloromethane (15 ml), at 0° C., was addeddropwise methanesulphonyl chloride (0.19 ml, 2.3 mmol). The reactionmixture was allowed to warm to room temperature and stirred for 16 h. Tothe reaction mixture was added water (10 ml) and the two layers wereseparated. The aqueous layer was extracted with dichloromethane (2×20ml) and the combined organic phases were washed with brine, dried(MgSO₄) and concentrated in vacuo to give the titled compound (600 mg).

Experimental MH⁺ 635.0; expected 635.0

1-15. (canceled)
 16. A method of preventing or treating a parasiticinfestation or infection in a non-human animal or plant comprisingadministration of a therapeutically effective amount of a compound ofFormula 1

or a pharmaceutically, veterinarily, or agriculturally acceptable saltthereof, wherein R¹ is phenyl optionally substituted by one or moregroups independently selected from the group consisting of halo, cyano,hydroxy, C₁₋₆ alkyl, C; haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₄.,alkanoyl, C₁₋₄, haloalkanoyl, —S(O)_(n)C₁₋₆alkyl, —S(O)_(n)C₁₋₆haloalkyl and pentafluorothio; R² is cyano; R³ is C₁₋₆ alkyl, C₁₋₆haloalkyl, or —(C₀₋₃alkylene)-phenyl; R⁴ is hydrogen, C₁₋₆ alkyl,C₁₋₆haloalkyl, —(C₀₋₃alkylene)-R⁷ or —(C₁₋₃alkylene)-R⁸; or R³ and R⁴taken together with the nitrogen and sulphur atoms to which they areattached form a 4 to 7-membered ring; R⁵ is hydrogen; R⁶ is C₁₋₆, alkylor C₁₋₆ haloalkyl; R⁷ is C₃₋₈cycloalkyl, —S(O)_(n)R⁹, phenyl, het,—CO₂R⁶ or C(O)N(R^(a))R^(h); R⁸ is hydroxy, alkoxy, C₁₋₆ haloalkoxy,cyano, —N(R^(a))R^(b) or —O—C(O)R⁶; R⁹ is C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₈cycloalkyl, —N(R^(a))R^(b), phenyl or het; R^(a) and R^(b)independently represent hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl or haloalkenyl, or R^(a) additionally is —(C₀₋₃alkylene C₃₋₈cycloalkyl, —(C₀₋₃alkylene)phenyl or —(C₀₋₃alkylene)-het, or togetherR^(a) and R^(b) form a 4- to 7-membered ring, optionally substituted byone or more groups independently selected from the group consisting ofhalo, hydroxy, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy andC₁₋₆haloalkoxy; n is the integer 0, 1 or 2; p is the integer 1 or 2;where het represents a four- to seven-membered heterocyclic group, whichis aromatic or non-aromatic and which contains one or more heteroatomsselected from the group consisting of nitrogen, oxygen, sulfur andmixtures thereof; where both phenyl and het may be optionallysubstituted, where the valence allows, by one or more substituentsindependently selected from the group consisting of halo, hydroxy,cyano, nitro, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkenyl, C₁₋₆haloalkenyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₃₋₈ cycloalkyl, C₁₋₆ alkanoyl, C₁₋₆haloalkanoyl, C₁₋₆ alkylcarbonyloxy, C₁₋₆ alkoxycarbonyl and N^(a)R^(b);where C₃₋₈cycloalkyl may be optionally substituted by one or more groupsindependently selected from the group consisting of halo, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆ alkenyl, hydroxy, C₁₋₆alkoxy and C₁₋₆haloalkoxy; andwhere any alkylene or alkenylene group may be optionally substituted byone or more halo.
 17. The method of claim 16 wherein R¹ of the Formula(I) compound is a phenyl group which bears chloro substituents at the 2-and 6-positions, and a substitutent at the 4-position selected from thegroup consisting of trifluoromethyl, difluoromethoxy, trifluoromethoxy,trifluoromethylthio and pentafluorothio.
 18. The method of claim 17wherein R³ is C₁₋₆ alkyl or C₁₋₆ haloalkyl.
 19. The method of claim 18wherein R³ is methyl.
 20. The method of claim 19 wherein R⁴ is hydrogen,methyl, ethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,methylsulfonyl, trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl,aminosulfonyl, N,N-dimethylaminosulfonyl, methylsulfonymethyl,cyclopropyl, cyclobutyl, cyclopropylmethyl,1-(trifluoromethyl)cyclopropylmethyl, cyanomethyl, methoxycarbonyl,triazolylethyl, pyrimidin-4-ylmethyl, 1,2,4-oxadiazol-3-ylmethyl,pyrazol-3-ylmethyl, 1-methyl-1H-imidazol-2-yl,5-methyl-isoxazol-3-ylmethyl, 2-pyridin-4-ylethyl, aminocarbonylmethyl,benzyl or 4-fluorobenzyl.
 21. The method of claim 16 wherein the Formula(I) compound is selected from the group consisting ofN-{3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1-pyrazol-4-yl}-1,1,1-trifluoro-N-methylmethanesulfonamide;N-{3-cyano-1-[2,6-dichloro-4-(trifluormethyl)phenyl]-1H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;N-{3-cyano-{[2,6-dichloro-4-pentafluorothiophenyl].H-pyrazol-4-yl}-N-(methylsulfonyl)methanesulfonamide;N-{3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}methanesulfonamide;andN-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-N-(2,2,2-trifluoroethyl)methanesulfonamide;or a pharmaceutically, veterinarily, or agriculturally acceptable saltthereof.
 22. The method of claim 16, wherein the non-human animal islivestock and companion animals.
 23. The method of claim 22 whereinlivestock is sheep, pigs, or cattle.
 24. The method of claim 22 whereinthe companion animal is a cat, dog, or horse.
 25. The method of claim16, wherein the parasitic infestation or infection in a non-human animalor plant is caused from arthropods, arachnids, nematodes, or helminthes.26. The method of claim 16, wherein the compound of Formula (I)administered orally, topically, or parenterally to the non-human animal.27. The method of claim 16, wherein the compound of Formula (I) is usedfor the control of plant pests.
 28. The method of claim 16, furthercomprising one or more biologically active compounds selected from thegroup consisting of insecticides, acaricides, anthelmintics, fungicides,nematocides, antiprotozoals, bactericides, growth regulators,entopathogenic bacteria, viruses, and fungi.